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Ivanchuk, Stacey M. "Expression of RET, GDNF and GDNFR-Ã in human development and disease." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq20655.pdf.
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DHALIWAL, PARVIN. "PARKINSON'S GDNF THERAPY AND OXIDATIVE STRESS." Thesis, The University of Arizona, 2008. http://hdl.handle.net/10150/190438.
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Roxo, Tiago Filipe Dias Santos. "Efeito anti-inflamatório do GDNF: qual a sua contribuição para a neuroprotecção dopaminérgica?" Master's thesis, Universidade da Beira Interior, 2013. http://hdl.handle.net/10400.6/1625.
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Microglia are the resident macrophages of the Central Nervous System and act as the main form of immune defence. Microglia can assume an activated state in case of inflammation, having its phagocytic activity increased, also releasing reactive oxygen species, in order to protect the Central Nervous System cells from injury. However, activated microglia has also been associated with neurodegeneration. Increased interleukin and cytokine levels have been described in neurodegenerative diseases, namely Parkinson’s disease, where the loss of dopaminergic neurons has been related to excessive microglial activation.
Soluble factors released by astrocytes are capable to modulate microglial reactivity. From these factors, glial cell line-derived neurotrophic factor (GDNF) stood out for its ability to protect dopaminergic neurons from injury, both in vitro an in vivo. Some studies have also demonstrated an anti-inflammatory action of GDNF, mediated by its receptor GFR1, suggesting that these two effects of GDNF may be related to each other. However, no study has provided a clear evidence for a cause-effect relationship between them.
Therefore, this work aims at elucidating the importance of GDNF control of microglial reactivity to the survival of dopaminergic neurons. The main strategy will be to block the action of GDNF specifically in microglial cells, through GFR1 silencing, and to evaluate its effect on the neuroprotective action of GDNF in the presence of an inflammatory stimuli. The expression of GFR1 in primary ventral midbrain microglia and N9 microglia cell line cultures was confirmed through immunochemistry and Western Blot. Silencing of GFR1, through siRNA, in N9 microglia cells was successfully accomplished and preliminary results suggest that silencing of this receptor in primary cultures of microglia is also doable. Co-cultures of N9 microglia cells and neuron-glia mixed cultures were exposed to different concentrations of LPS which induced a selective dopaminergic injury. Under these conditions, an increase in microglial reactivity was observed. Additional experiments will be necessary to achieve the main goal of this work. However, these results will support future experiments in order to elucidate the relevance of the anti-inflammatory effect of GDNF on dopaminergic neuroprotection.As microglias são os macrófagos residentes do Sistema Nervoso Central e actuam como a principal forma de defesa imunitária. Podem assumir um estado denominado activado, tendo a sua capacidade fagocítica aumentada e produzindo espécies reactivas de oxigénio, com o propósito de proteger as células do Sistema Nervoso Central. No entanto, este estado activado tem sido também relacionado com um processo neurodegenerativo. Aumentos dos níveis de interleucinas e citocinas têm sido descritos em doenças neurodegenerativas, nomeadamente na doença de Parkinson, onde a perda de neurónios dopaminérgicos tem sido associada a uma excessiva activação microglial. Factores solúveis libertados pelos astrócitos mostraram ser capazes de modular a reactividade microglial. Destes factores, o factor derivado de uma linha de células da glia (GDNF) destacou-se pela sua capacidade em proteger os neurónios dopaminérgicos, tanto in vitro como in vivo. Alguns estudos têm também demonstrado uma acção anti-inflamatória do GDNF, mediada pelo receptor GFR1, sugerindo que possa existir uma relação entre estes dois efeitos. No entanto, até ao momento, não foi ainda demonstrada uma relação de causaefeito entre eles. Assim, este trabalho tem como objectivo elucidar a importância do controlo da reactividade microglial pelo GDNF na sobrevivência dos neurónios dopaminérgicos. A estratégia principal será impedir a acção do GDNF especificamente na microglia, através do silenciamento do receptor GFR1, e avaliar o efeito deste silenciamento na acção neuroprotectora do GDNF após aplicação de um estímulo inflamatório. A expressão de GFR1 em culturas primárias de microglia do mesencéfalo ventral e numa linha celular de microglia N9 foi confirmada por imunocitoquímica e Western Blot. O silenciamento do receptor GFR1 na linha celular de microglia N9 foi alcançado com sucesso e resultados preliminares sugerem que o silenciamento deste receptor em culturas primárias de microglia é também possível. A exposição de co-culturas de microglia N9 e culturas mistas de neurónios e glia do mesencéfalo ventral a diferentes concentrações de LPS induziu a morte selectiva de neurónios dopaminérgicos. Paralelamente, foi possível observar um aumento da reactividade microglial. Experiências adicionais serão necessárias para atingir o objectivo principal deste trabalho. No entanto, estes resultados servirão de base para, em futuras experiências, elucidar a relevância do efeito anti-inflamatório do GDNF na neuroprotecção dopaminérgica.
4
Trupp, Miles. "Neurotrophic signalling by GDNF and its receptors /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19980602trup.
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Fink, Erin Nicole. "GM1 signaling through the GDNF receptor complex." Columbus, Ohio : Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1198013799.
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Chermenina, Maria. "GDNF and alpha-synuclein in nigrostriatal degeneration." Doctoral thesis, Umeå universitet, Histologi med cellbiologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-91811.
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Parkinson’s disease is a common neurological disorder with a complex etiology. The disease is characterized by a progressive loss of dopaminergic cells in the substantia nigra, which leads to motor function and sometimes cognitive function disabilities. One of the pathological hallmarks in Parkinson’s disease is the cytoplasmic inclusions called Lewy bodies found in the dopamine neurons. The aggregated protein α-synuclein is a main component of Lewy bodies. In view of severe symptoms and the upcoming of problematic side effects that are developed by the current most commonly used treatment in Parkinson’s disease, new treatment strategies need to be elucidated. One such strategy is replacing the lost dopamine neurons with new dopamine-rich tissue. To improve survival of the implanted neurons, neurotrophic factors have been used. Glial cell line-derived neurotrophic factor (GDNF), which was discovered in 1993, improves survival of ventral mesencephalic dopamine neurons and enhances dopamine nerve fiber formation according to several studies. Thus, GDNF can be used to improve dopamine-rich graft outgrowth into the host brain as well as inducing sprouting from endogenous remaining nerve fibers. This study was performed on Gdnf gene-deleted mice to investigate the role of GDNF on the nigrostriatal dopamine system. The transplantation technique was used to create a nigrostriatal microcircuit from ventral mesencephalon (VM) and the lateral ganglionic eminence (LGE) from different Gdnf gene-deleted mice. The tissue was grafted into the lateral ventricle of wildtype mice. The results revealed that reduced concentrations of GDNF, as a consequence from the Gdnf gene deletion, had effects on survival of dopamine neurons and the dopamine innervation of the nigrostriatal microcircuit. All transplants had survived at 3 months independently of Gdnf genotype, however, the grafts derived from Gdnf gene-deleted tissue had died at 6 months. Transplants with partial Gdnf gene deletion survived up to 12 months after transplantation. Moreover, the dopaminergic innervation of striatal co-grafts was impaired in Gdnf gene-deleted tissue. These results highlight the role of GDNF for long-term maintenance of the nigrostriatal dopamine system. To further investigate the role of GDNF expression on survival and organization of the nigrostriatal dopamine system, VM and LGE as single or combined to double co-grafts created from mismatches in Gdnf genotypes were transplanted into the lateral ventricle of wildtype mice. Survival of the single grafts was monitored over one year using a 9.4T MR scanner. The size of single LGE transplants was significantly reduced by the lack of GDNF already at 2 weeks postgrafting while the size of single VM was maintained over time, independently of GDNF expression. The double grafts were evaluated at 2 months, and the results revealed that lack of GDNF in LGE reduced the dopamine cell survival, while no loss of dopamine neurons was found in VM single grafts. The dopaminergic innervation of LGE was affected by absence of GDNF, which also caused a disorganization of the striatal portion of the co-grafts. Small, cytoplasmic inclusions were frequently found in the dopamine neurons in grafts lacking GDNF expression. These inclusions were not possible to classify as Lewy bodies by immunohistochemistry and the presence of phospho-α-synuclein and ubiquitin; however, mitochondrial dysfunction could not be excluded. To further study the death of the dopamine neurons by the deprivation of GDNF, the attention was turned to how Lewy bodies are developed. With respect to the high levels of α-synuclein that was found in the striatum, this area was selected as a target to inject the small molecule – FN075, which stimulates α-synuclein aggregation, to further investigate the role of α-synuclein in the formation of cytoplasmic inclusions. The results revealed that cytoplasmic inclusions, similar to those found in the grafts, was present at 1 month after the injection, while impairment in sensorimotor function was exhibited, the number of dopamine neurons was not changed at 6 months after the injection. Injecting the templator to the substantia nigra, however, significantly reduced the number of TH-positive neurons at 3 months after injection. In conclusion, these studies elucidate the role of GDNF for maintenance and survival of the nigrostriatal dopamine system and mechanisms of dopamine cell death using small molecules that template the α-synuclein aggregation.
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Oliveira, Julieta Conceição Mendes Borges. "GDNF e GPER: novas ferramentas no controlo da neuroinflamação?" Master's thesis, Universidade da Beira Interior, 2013. http://hdl.handle.net/10400.6/1628.
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As células microgliais, os macrófagos residentes no sistema nervoso central, são responsáveis pela resposta imune inata. Quando são moderadamente ativadas, realizam funções vitais, fagocitando células mortas e removendo detritos celulares e toxinas. No entanto, uma ativação persistente destas células pode resultar numa desregulação da sua atividade. Elas podem tornar-se reativas e contribuir para a morte neuronal. Evidências crescentes sugerem que a inflamação e o stress oxidativo mediado pela microglia reativa desempenham um papel fundamental na progressão de várias doenças neurodegenerativas, como a doença de Parkinson. Tanto o fator neurotrófico derivado de uma linha de células da glia (GDNF) como os estrogénios são relatados por atuar na microglia, controlando a sua ativação excessiva.
Um estudo anterior do nosso grupo mostrou que o GDNF presente em meio condicionado de astrócitos consegue inibir a reatividade microglial induzida pelo Zymozan A numa cultura primária de microglia do mesencéfalo ventral. O primeiro objetivo do presente trabalho foi o de verificar se a presença de neurónios, lesados ou não, poderia influenciar este efeito anti-inflamatório exercido pelo GDNF. Utilizando o mesmo tipo de cultura verificámos que o condicionamento na presença de neurónios reverteu a inibição da produção de NO exercida pelos meios condicionados apenas por astrócitos na microglia estimulada com LPS. Este diferente efeito dos dois meios poderá estar relacionado com o facto de os meios condicionados por culturas mistas de neurónios e astrócitos apresentaram níveis mais baixos de GDNF que os meios condicionados apenas por astrócitos.
Por outro lado, estudos utilizando culturas primárias de microglia, bem como linhas celulares, demonstraram a capacidade do estrogénio para atenuar a ativação da microglia, em termos de atividade fagocítica, produção de espécies reativas de oxigénio e de azoto, bem como de outros fatores da cascata inflamatória. Está já descrita a capacidade dos estrogénios ativarem os recetores de estrogénio α e β presentes na microglia. No entanto, mais recentemente identificou-se um recetor de estrogénios transmembranar, o recetor de estrogénio acoplado à proteína G (GPER). O segundo objetivo do trabalho foi esclarecer a participação do GPER no controle da reatividade microglial mediada pelo estradiol. Utilizando uma linha celular de microglia N9, um agonista e um antagonista seletivos do recetor, verificamos que a ativação do GPER promoveu a migração das células microgliais e reduziu significativamente os parâmetros de reatividade microglial estudados. Estes resultados sugerem que o GPER pode ser um importante alvo terapêutico para doenças neurodegenerativas e neuroinflamatórias, especialmente nos homens, nos quais a terapia com estrogénio não é viável.Microglial cells, the macrophages resident in the central nervous system, are responsible for the innate immune response. When moderately activated, these cells perform vital functions such as phagocytosing dead cells and removing cell debris and toxins. However, a persistent activation of these cells may result in deregulation of its activity. They can become reactive and contribute to neuronal death. Increasing evidences suggests that inflammation and oxidative stress mediated by reactive microglia play a key role in the progression of various neurodegenerative diseases such as Parkinson's disease. Both the glial cell line derived neurotrophic factor (GDNF) and estrogens are reported to play a role in this process and to control excessive activation of microglia. A previous study from our group that used a primary culture of ventral midbrain microglia showed that GDNF present in medium conditioned by astrocytes can inhibit microglial reactivity induced by Zymozan A. The first objective of the present study was to verify if the presence of neurons, injured or not, could influence this anti-inflammatory effect exerted by GDNF. Using the same culture we found that media conditioned by both astrocytes and neurons was no longer capable of inhibiting NO production on LPS-stimulated microglia. The different effects of the two media may be related to the fact that the media conditioned by cultures of neurons and astrocytes presented lower levels of GDNF as compared with media conditioned only by astrocytes. On the other hand, studies using primary cultures and microglia cell lines demonstrated the ability of estrogen to attenuate parameters of microglial activation such as phagocytic activity, production of reactive oxygen and nitrogen, as well as other factors inflammatory cascade. The ability of estrogens to regulate estrogen receptors α and β present in microglia was previously described. However, more recently a transmembrane estrogen receptor, the G-protein coupled estrogen receptor (GPER) was identified. The objective of the second part of the present work was to clarify the involvement of GPER in the control microglial reactivity mediated by estradiol. Using the N9 microglial cell line, an agonist and an antagonist of GPER receptor, we found that GPER activation promoted the migration of microglial cells and significantly reduced the various parameters of microglial reactivity evaluated. Taken together these results suggest that GPER can be an important therapeutic target for neurodegenerative and neuroinflammatory diseases, especially in males, for whom estrogen therapy is not feasible.
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Fonseca, Ana Paula da Silva. "Contribuição do GDNF para a neuroprotecção exercida pelo estrogénio." Master's thesis, Universidade da Beira Interior, 2010. http://hdl.handle.net/10400.6/799.
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A doença de Parkinson é a segunda doença neurodegenerativa mais
comum, depois do Alzheimer, e caracteriza-se principalmente pela perda
progressiva de neurónios dopaminérgicos na Substantia Nigra. Numerosos
trabalhos reportaram a maior prevalência e incidência desta doença no sexo
masculino, relativamente ao sexo feminino. Estudos envolvendo a reposição
com estrogénios em ratos fêmea ovariectomizados, atribuíram esta diferença
de incidências ao efeito neuroprotectivo do estrogénio. No entanto, o grau de
protecção exercida por níveis fisiológicos desta hormona permanece
desconhecido.
Os estrogénios também têm sido implicados na regulação da expressão
de factores neurotróficos, o que pode estar na origem dos seus efeitos
neuroprotectores. O factor neurotrófico derivado de uma linha de células da glia
(GDNF) é um dos factores neurotróficos regulados pelo estrogénio, que foi
implicado na neuroprotecção e regeneração na via nigroestriatal, actuando
como um potente factor de sobrevivência para os neurónios dopaminérgicos,
que são alvo de degeneração na doença de Parkinson.
De forma a esclarecer o papel dos níveis endógenos de estrogénio na
protecção da via nigroestriatal, utilizámos como modelo da doença de
Parkinson a 6-hidroxidopamina, e estudámos de que forma a remoção dos
ovários em fêmeas férteis interferiu com a extenção da lesão dopaminérgica
induzida pela toxina. As fêmeas Wistar foram ovariectomizadas e 3 semanas
após a cirurgia os animais foram injectados estereotaxicamente, no estriado, com 6-hidroxidopamina. A extensão da lesão foi avaliada através da contagem
de células que expressavam o marcador dopaminérgico tirosina hidroxilase,
por imunohistoquimica, assim como pelos níveis de expressão desta proteína,
por western blot, tanto na Substantia Nigra como no estriado. Os níveis
plasmáticos de estradiol também foram quantificados. De forma a determinar a
a existência de relação entre os níveis de estradiol, a expressão de GDNF e a
extensão da lesão dopaminérgica, também foi estudada a expressão do factor
neurotrófico GDNF.
Os nossos resultados sugerem fortemente que o estrogénio produzido
endogenamente, assim como o GDNF, estão associados com níveis
aumentados de tirosina hidroxilase estriatal, um marcador de sobrevivência da
célula dopaminérgica.Parkinson´s disease is the second most common neurodegenerative disorder after Alzheimer and is mainly characterized by a progressive and selective depletion of dopamine neurons in the Substantia Nigra. Numerous studies have reported a greater prevalence and incidence of PD in men than in women. Studies involving estrogen treatment of ovariectomised rodents attribute this largely to the neuroprotective effets of estrogen. However, a neuroprotective role for physiologic levels of circulating estrogen in females is less clear. Estrogens have also been shown to regulate the expression of neurotrophic factors, like glial cell line-derived neurotrophic factor (GDNF), which might mediate their neuroprotective effects. GDNF produces neuroprotective and regenerative effects in the nigrostriatal pathways, acting as a potent survival factor for dopaminergic neurons that degenerate in Parkinson’s disease. In order to clarify the role of endogenous levels of estrogens in protecting the nigrostriatal pathway, we used the 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease and tested how the removal of ovaries in fertile females interferes with extent of the dopaminergic lesion induced by 6-OHDA. Female Wistar rats were ovariectomised and 3 weeks after the surgery the animals were stereotaxically injected in the striatum with 6-OHDA. The extent of the lesion was assessed by counting the cells expressing the dopaminergic marker tyrosine hydroxylase by imunohistochemistry and also the expression levels of this protein by Western blot in both the Substantia Nigra and the striatum. The plasma levels of estradiol were also quantified. To determine if there was a relationship between estradiol levels, the expression of GDNF and the extent of the dopaminergic lesion, we also studied the expression of the neurotrophic factor GDNF. Our findings strongly suggest that endogenously produced estrogens and GDNF are associated with increased levels of striatal tyrosine hydroxylase, a marker of dopaminergic cell survival.
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Wartiovaara, Kirmo. "GDNF and p75 neurotrophin receptor in development and disease." Helsinki : University of Helsinki, 1999. http://ethesis.helsinki.fi/julkaisut/laa/biola/vk/wartiovaara/.
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Åkerud, Peter. "GDNF family ligands and neural stem cells in Parkinson's disease /." Stockholm : [Karolinska Univ. Press], 2001. http://diss.kib.ki.se/2001/91-7349-042-3/.
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Batista, Carla Isabel Soares. "Regulação dos níveis de GDNF na substantia nigra pelo estradiol." Master's thesis, Universidade de Aveiro, 2007. http://hdl.handle.net/10773/731.
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Mestrado em ToxicologiaO stress oxidativo ao nível da via nigroestriatal é reconhecido como uma das causas da degeneração dos neurónios dopaminérgicos da substantia nigra na doença de Parkinson (DP), sendo o efeito protector do estradiol recorrentemente associado à protecção contra o stress oxidativo. A acção protectora do estradiol na via nigroestriatal pode ainda envolver outros efeitos, tais como modulação da expressão de factores neurotróficos cuja capacidade de promover a sobrevivência neuronal é sobejamente conhecida. Neste trabalho analisámos a regulação dos níveis do factor neurotrófico derivado de uma linha de células da glia (GDNF) pelo 17β-estradiol na substantia nigra e determinámos qual a contribuição específica deste efeito para a acção neuroprotectora da hormona. Adicionalmente, estudámos a modulação do efeito do 17β-estradiol na expressão de GDNF por agentes oxidantes, levodopa (L-DOPA) e H2O2. Para determinar os níveis de GDNF procedemos a análise de Western-Blot em extractos de células pós-natais de substantia nigra em cultura após incubação com 17ß-estradiol. Realizámos estudos in vivo para determinar de que forma o 17ß-estradiol afecta a acção da toxina dopaminérgica 6-hidroxidopamina (6-OHDA), quer ao nível da viabilidade das células dopaminérgicas, como ao nível da expressão dos níveis de GDNF. Os resultados obtidos permitiram concluir que, em células pós-natais de substantia nigra em cultura, o 17ß-estradiol promoveu o incremento da expressão do GDNF pelos astrócitos, provavelmente via ligação a receptores membranares. Verificámos ainda que os efeitos do estradiol parecem ser potenciados pela a exposição a L-DOPA e H2O2. In vivo, o estradiol protegeu as células dopaminérgicas da substantia nigra da lesão causada por 6-OHDA, possivelmente através da estimulação da síntese de GDNF observada nestas condições. ABSTRACT: Estradiol is currently considered a neuroprotector agent of nigral dopaminergic neurons. Oxidative stress in the nigrostriatal pathway has been associated with the development of Parkinson disease and the protective effect of estradiol is thought to be associated with a defence against oxidative stress. The protection promoted by estradiol in nigrostriatal pathway may also be coupled to the expression of neurotrophic factors, molecules recognized by its capability to promote neuron survival. In this study we analysed how 17ß-estradiol regulates nigral glial cell line deriv GDNF levels and evaluated the contribution of this effect to the neuroprotective action of this hormone. We also assessed how levodopa (L-DOPA) and H2O2 modulated the effect of estradiol on GDNF expression. Western-Blot analysis was used to determine GDNF levels in cultured substantia nigra cells after incubation with 17ß-estradiol. Using in vivo studies we evaluated how 17ß-estradiol affects the action of the dopaminergic toxin - 6- hidroxydopamine (6-OHDA) on the dopaminergic cell viability and the expression of GDNF. Taken together the results showed that, in cultured postnatal substantia nigra cells, 17ß-estradiol promoted the increase of GDNF expression by astrocytes through activation of putative membrane receptors. Exposure to the oxidative agents L-DOPA and H2O2 augmented the effect of estradiol. In vivo, estradiol protected nigral dopaminergic cells from 6-OHDA induced injury, possibly through stimulation of GDNF synthesis.
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Cameron, Nicholas John. "Developing Olfactory Ensheathing Cells for ex vivo Delivery of GDNF." Thesis, Griffith University, 2010. http://hdl.handle.net/10072/365205.
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Olfactory ensheathing cells have well described neurotrophic properties and can promote repair of damaged nerves in the central nervous system. Genetically engineering these cells to deliver therapeutic proteins could ‘supercharge’ their existing abilities to repair damaged nerves and prevent neurodegeneration in disease. The present study used retroviral vectors to engineer human olfactory ensheathing cells to co-express the potent neurotrophin GDNF and reporter genes under a tetracycline-inducible promoter. The goal here was to provide proof of concept for using olfactory ensheathing cells (OECs) for controlled ex vivo delivery of GDNF in preclinical studies. Until now, OECs from the olfactory mucosa have not been examined or developed for this purpose. Here a systematic evaluation of OECs revealed their suitability for developing ex vivo gene therapies. Olfactory ensheathing cells from rats and humans were successfully purified from the olfactory mucosa by p75NTR immunopanning and did not express secreted GDNF protein prior to genetic modification. The immunopanning method did not purify putative neural precursors or stem cells from the human source tissue. Lentiviral vectors incorporating bi-cistronic gene expression cassettes directed drug-inducible co-expression of GDNF and reporter gene in transduced OECs. Here for the first time the foot and mouth disease virus 2A cleavage factor was used to co-express GDNF and reporter genes in human OECs. Biological activity of GDNF and reporter genes (EGFP and β-Galactosidase) was not affected by 2A cleavage in transduced OECs. Owing to robust reporter gene expression in these cells, highly purified cultures of drug-inducible and constitutive expressing OECs were isolated by fluorescence activated cell sorting. In the inducible cell lines, more than 20-fold induction of gene expression was seen after treatment with minocycline however, unsatisfactory baseline expression or ‘leakage’ was observed in the absence of minocycline. Cells constitutively co-expressing GDNF and EGFP were then transplanted into the intact rat striatum. After 9 days, transplanted OECs expressed transgenes, but the majority of grafted cells died. Overcoming the poor cell survival and leakage of expression in inducible cells must precede transplanting these cells in animal models of disease. In conclusion, a robust method for co-expressing therapeutic genes in OECs for preclinical ex vivo gene therapy studies was developed using 2A cleavage and lentiviral vectors. The results present a strong case for using OECs as vehicles to deliver therapeutic genes but also highlight shortcomings of drug-inducible gene expression systems.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical Sciences
Science, Environment, Engineering and Technology
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Nevalainen, Nina. "Dysfunction in the nigrostriatal system : effects of L-DOPA and GDNF." Doctoral thesis, Umeå universitet, Histologi med cellbiologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-64149.
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Parkinson’s disease is a common neurodegenerative disorder caused by nigrostriatal dopamine loss, with motor deficiencies as the primary outcome. To increase the striatal dopamine content, patients are treated with 3,4-dihydroxyphenyl-l-alanine (l-DOPA). Beneficial relief of the motor symptoms is achieved initially, although the efficacy is lost with time and severe side effects, referred to as l-DOPA-induced dyskinesia, manifest in the majority of patients. Biological mechanisms responsible for the dopaminergic degeneration and the upcoming of dyskinesia are still unclear, and thus knowledge regarding critical factors for maintenance of the nigrostriatal system as well as neurochemical changes upon chronic l-DOPA is urgent. The present work aims at studying the importance of glial cell line-derived neurotrophic factor (GDNF) for nigrostriatal preservation, and the involvement of the dopaminergic, serotonergic, and glutamatergic systems in l-DOPA-induced dyskinesia. Effects from different levels of GDNF expression were evaluated on fetal mouse nigrostriatal tissue in a grafting study. In GDNF gene-deleted grafts, degeneration of the entire nigrostriatal system was evident at 6 months. In grafts with partial GDNF expression, significant loss of dopamine neurons was observed at later time points, although deviant findings in the dopamine integrity such as reduced innervation capacity and presence of intracellular inclusions-like structures were already present at earlier stages. The results emphasize GDNF as a crucial factor for long-term maintenance of the nigrostriatal system. Furthermore, striatal neurochemical alterations upon chronic l-DOPA treatment were studied in hemiparkinsonian rats using in vivo voltametry. The findings demonstrated impaired dopamine as well as glutamate releases in dyskinetic subjects, with no effects from acute l-DOPA administration. Conversely, in l-DOPA naïve dopamine-lesioned animals, dopamine release was increased and glutamate release attenuated upon a l-DOPA challenge. Moreover, l-DOPA-derived dopamine release was demonstrated to originate from serotonergic nerve fibers in the dopamine-lesioned striatum, an event that contributes significantly to dopamine levels also in intact striatum, and thus, is not a consequence from dopamine depletion. Assessment of serotonergic nerve fibers in l-DOPA treated animals and in a grafting study concluded that nerve fiber density was not affected by chronic l-DOPA treatment, nevertheless, dysfunction of this system can be suspected in dyskinetic animals since dopamine release was impaired and regulation of glutamate release by serotonergic 5-HT1A receptor activation was achieved in normal but not in dyskinetic animals. Furthermore, the selective serotonin reuptake inhibitor, fluoxetine, attenuated l-DOPA-induced dyskientic behavior, an effect that was demonstrated to be mediated via 5-HT1A receptors. In conclusion, dysmodulation of multiple transmitter systems is evident in LID.
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Boucher, Timothy John. "The GDNF family of neurotrophic factors : effects on adult sensory neurons." Thesis, King's College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272413.
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Hohmeier, Tim [Verfasser]. "Die enterische Muskulatur als Quelle des neurotrophen Faktors GDNF / Tim Hohmeier." Gießen : Universitätsbibliothek, 2015. http://d-nb.info/1080661387/34.
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Klein, Pontus. "Functions of GDNF/Ret signaling in models of autosomal recessive Parkinson’s disease." Diss., Ludwig-Maximilians-Universität München, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-166901.
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Mikaels, Åsa. "Expression and function of GDNF family ligands and receptors in the nervous system /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4885-2/.
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Doxakis, Epaminondas. "Regulation of expression and role of the GDNF family receptors in neuronal development." Thesis, University of St Andrews, 1999. http://hdl.handle.net/10023/14779.
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The aim of this project was to determine the temporal and spatial pattern of expression of GDNF family receptors in the developing embryo, with particular emphasis on expression in the peripheral nervous system, and to investigate how expression of receptor mRNAs is regulated in developing neurons. It was hoped that the data obtained would prove useful in further characterizing the role that the GDNF family of neurotrophic factors play in embryonic development. Semi- quantitative PCR revealed that GFRα-1, GFRα-2, GFRα-4 and ret mRNAs are widely distributed with both complementary and overlapping, though distinct, patterns of expression in the chicken embryo during development. Different populations of PNS neurons display different levels of responsiveness to GDNF and NTN and their sensitivity to these factors change throughout development. Examination of receptor expression by quantitative RT-PCR revealed that neurons that are more sensitive to GDNF express higher levels of GFRα-1 mRNA than GFRα-2 mRNA, and neurons that are more sensitive to NTN express higher levels of GFRα-2 mRNA compared to GFRα-1 mRNA. However, developmental changes in responsiveness of a population of neurons to these factors are not consistently paralleled by changes in the relative levels of GFRα transcripts. Furthermore, all neuronal populations express relatively high levels of ret mRNA. These results indicate the responsiveness of PNS neurons to GDNF and NTN is in part governed by the relative levels of expression of their GPI-linked receptors. To determine how the expression of the GDNF family receptors is regulated, embryonic neurons were cultured under different experimental conditions. I found that GFRα-1, GFRα-2, GFRα-4 and ret mRNAs are not significantly regulated by GDNF and/or NTN. However, depolarizing levels of KC1 cause marked changes in the expression of GFRα mRNAs. The effects of KCl are inhibited by L-type Ca2+ channel antagonists, suggesting that they were mediated by elevation of intracellular free Ca2+. KCl treatment increases the response of neurons to GDNF and decreases their response to NTN. There is no marked effect of depolarization on ret mRNA expression.
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Rossi, Jari. "Roles of GDNF family receptor GFRa[alpha]2 in the peripheral nervous system." Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/eri/biote/vk/rossi/.
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Charlet-Berguerand, Nicolas. "Etude de la régulation de l'épissage alternatif des pré-messagers RET, GFRalpha1, cTNT et C1C1." Paris 7, 2003. http://www.theses.fr/2003PA077023.
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Vargas, Vivian. "Expression and function of GDNF family ligands and their receptors by human immune cells." Diss., lmu, 2004. http://nbn-resolving.de/urn:nbn:de:bvb:19-22922.
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Brodbeck, Stephan [Verfasser]. "Charakterisierung des Transkriptionsfaktors SIX2 und seiner Bindungsstellen im GDNF- und Six2-Promotor / Stephan Brodbeck." Karlsruhe : KIT-Bibliothek, 2003. http://d-nb.info/1198221607/34.
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YAMADA, KIYOFUMI. "PRO-ADDICTIVE AND ANTI-ADDICTIVE FACTORS FOR DRUG DEPENDENCE." Nagoya University School of Medicine, 2008. http://hdl.handle.net/2237/10542.
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Nevalainen, Nina. "Effects of glial cell line-derived neurotrophic factor (GDNF) on mouse fetal ventral mesencephalic tissue." Thesis, Mälardalen University, Department of Biology and Chemical Engineering, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:mdh:diva-615.
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The symptoms of Parkinson's disease occur due to degeneration of dopamine neurons in substantia nigra. It has been demonstrated that glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor when it comes to protect and enhance survival of dopamine neurons in animal models of Parkinson's disease. The aim of this study was to evaluate short- and long-term effects of GDNF on survival and nerve fiber outgrowth of dopamine cells and astrocytic migration in mouse fetal ventral mesencephalic (VM) tissue. Primary tissue cultures were made of mouse fetal VM tissue and evaluated at 7 and 21 days in vitro (DIV) in terms of dopaminergic nerve fiber outgrowth and astrocytic migration when developed with GDNF present, partially, or completely absent. The results revealed that VM tissue cultured in the absence of GDNF did not exhibit any significant differences in migration of astrocytes or dopaminergic nerve fiber outgrowth neither after 7 DIV nor after 21 DIV, when compared with tissue cultured with GDNF present. Migration of astrocytes and dopaminergic nerve fiber outgrowth reached longer distances when tissue was left to develop for 21 DIV in comparison with 7 DIV. In order to study the long-term effects of GDNF, mouse fetal dopaminergic tissue was transplanted into the ventricles of adult mice and evaluated after 6 months. No surviving dopamine neurons were present in the absence of GDNF. In contrast dopamine neurons developed with GDNF did survive, indicating that GDNF is an essential neurotrophic factor when it comes to long-term dopamine cell survival. More cases have to be assessed in the future in order to strengthen the findings. Thus, transplanted dopamine neurons will be assessed after 3 and 12 months in order to map out when dopamine neurons deprived of GDNF undergo degeneration.
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Veit, Christine. "Charakterisierung der Regulation der gerichteten Migration und Invasion humaner Pankreaskarzinomzellen durch den neuronalen Wachstumsfaktor GDNF." [S.l. : s.n.], 2002. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB10283627.
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Basu, Shubhayu. "Effects of three dimensional structure of tissue scaffolds on animal cell culture." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1092689986.
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Thesis (Ph. D.)--Ohio State University, 2004.Title from first page of PDF file. Document formatted into pages; contains xviii, 236 p.; also includes graphics (some col.). Includes bibliographical references (p. 194-211). Available online via OhioLINK's ETD Center
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Fuqua, Joshua Lee. "STUDIES OF THE EFFECTS OF DOPAMINE NEURON STIMULATING PEPTIDES IN RODENT MODELS OF NORMAL AND DYSFUNCTIONAL DOPAMINERGIC SYSTEMS." UKnowledge, 2010. http://uknowledge.uky.edu/gradschool_diss/90.
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A theoretical post-translational processing model of the proprotein form of glial cell line-derived neurotrophic factor (GDNF) likely produces three biologically active peptides. The three prospective peptides formed are 5, 11, and 17 amino acid peptides, entitled dopamine neuron stimulating peptide -5 (DNSP-5), -11 (DNSP-11), and -17 (DNSP-17), respectively. The DNSPs were hypothesized to increase dopaminergic neuron function because of their relationship to GDNF: a molecule with established neurotrophic actions on dopaminergic neurons. The DNSPs have the potential to provide a therapeutic molecule similar to GDNF, but with increased ease of delivery and improved bioavailability.
Neurochemical effects of DNSPs were examined in the nigrostriatal pathway of normal Fischer 344 rats, and DNSP-11 was found to be the most effective in increasing dopamine neurochemical function. Striatal microdialysis, four weeks after a single intranigral administration of DNSP-11, showed significant increases in the baseline concentrations of dopamine, DOPAC, and HVA. In addition, both, potassium and d-amphetamine-evoked dopamine overflow were significantly increased.
DNSP-11 was delivered intranigrally to aged Fischer 344 rats to examine DNSP-11’s ability to improve dopaminergic function in aged dopamine neurons. DNSP-11 affected striatal dopaminergic function 28 days after treatment by decreasing baseline concentrations of dopamine and evoked dopamine release.
Investigation of DNSP-11 continued, using two models of neurotoxin-induced dopamine neuron loss that model cell loss associated with Parkinson’s disease. The neuroprotective properties of DNSP-11 were evaluated by delivering DNSP-11 prior to the neurotoxic insult. DNSP-11 treatment was unable to protect dopaminergic neurons, but significantly increased dopamine metabolism. In a model of severe dopamine neuron loss, DNSP-11 treatment significantly improved apomorphine-induced rotation behavior, indicative of alterations in the function of nigrostriatal dopaminergic neurons. Subsequent examination of dopamine content within the SN revealed significant increases in dopamine and DOPAC levels by DNSP-11.
Taken together, DNSP-11 treatments modified dopamine neurochemistry in all investigated rodent models. The observed long-term alterations of dopamine neurochemistry by DNSP-11 and subsequent behavioral changes support a potential use for DNSP-11 as a therapeutic for dopaminergic cell loss. Increased dopaminergic function by DNSP-11 is evidence for the novel concept that peptides contained within the prodomain of trophic factors can have neurotrophic actions.
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Cristofaro, Rosalba. "GENETICA MOLECOLARE, EPIDEMIOLOGIA, PATOGENESI DEL RENE MIDOLLARE A SPUGNA." Doctoral thesis, Università degli studi di Padova, 2012. http://hdl.handle.net/11577/3426283.
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Medullary Sponge Kidney (MSK) was recognized for the first time in Padua, in 1939 by Lenarduzzi utilizing a new urography technique and subsequently described in 1949 by Cacchi and Ricci respectively urologist and pathologist at the University of Padua. Since its association with other congenital renal and extrarenal malformations, MSK may be considered among the congenital renal malformations also due to the presence of precalyceal ectasia of collecting ducts . The renal function and life span are normal in MSK patients, neverthless MSK is often complicated by the development of nephrocalcinosis and nephrolithiasis. The pathogenesis of MSK has not been totally elucidated but many authors agree that it is a congenital disease with delayed expression. A genetic cause for MSK could be suggested by the description of some familial cases, by its link to the group of congenital malformations and by its association with other inherited diseases. Recently, the discovery of the genes responsible for this disease has attracted the attention of our group work and in particular of my PhD work. The working hypothesis is that MSK is the consequence of a disturbance in the ureteric bud- metanephric blastema interface, which might be due either to disease- causing mutation/ specific polymorphism of RET, GDNF and other genes involved in the inter-facing, or to particular RET/GDNF genotype interaction. The results of direct sequencing and RFLP testing of GDNF on a population of 112 , unrelated of Venetian origin MSK patients selected on the basis of strict urographic criteria led to the identification of a rare variant of GDNF promoter region (27+18G>A) significantly associated with MSK (p=0.02). In addition, the possibility to extend GDNF screening to the family members of MSK patients carrying rare variants allowed us to discover that the variants were inherited and that they were associated with the MS K phenotype. In the second part of the study it has been placed attention to the familial cases of MSK. Sampling 50 cases from the cohort of 112 sporadic MSK cases, and analyzing family members of the 1° and 2° generations by ultrasonography and /or UroTAC, we found that in 27 families MSK was inherited as an autosomal dominant trait, with variable expressivity and incomplete penetrance. In 19 families the screening of GDNF gene was conducted and, in addition, the screening of Six1, Spry1 and PAX2 genes that are involved in nephrogenesis with an important role in the mechanisms of GDNF regulation was performed. Sequencing of exon and intron boundaries of GDNF gene on the 19 families did not reveal any nucleotide substitutions or rare variants. Similarly, no causative mutation was found for Six1, Spry1 and Pax2. For Spry1 and Pax2 polymorphisms have been found but without any significance in the allele frequency as compared to control population. Another objective of the study was to understand the functional significance od GDNF rare variants in the context of MSK phenotype. The removal of a renal cell carcinoma in a MSK patient with the GDNF intronic (-27+18 G / C )rare variant gave us the opportunity to study MSK papillary cells in culture. We observed an exceptional phenomenon, the appearance of an osteogenic-like phenotype with deposition of calcium phosphate. We wonder if the down-regulation of GDNF expression that was lower in MSK cells in respect to control cells were the culprit of the observed phenomenon. To investigate if GDNF down-regulation most likely due to the mutation in the promoter region, may have had a role in the process of spontaneous calcification, we have stably silenced GDNF gene in human renal epithelial cells (HK2), through the technique of RNA interference. Preliminary data from these experiments showed in the silenced HK2 cells cultured under osteogenic conditions the presence of aggregates that Won Kossa staining and SEM analysis confirmed to be of Ca2PO4. The presence of calcium phosphate deposits were not observed in control negative as well as in silenced clones cultured in normal conditions, while in control negative cells under osteogenic stimulation few deposits were seen, however in lower number in respect to silenced cells. Although preliminary, our results suggest that GDNF down regulation in HK2 cells may favor Ca2PO4 deposition throught a mechanism not yet identified. Our hypothesis is that apoptosis might be the key.IL Rene con Midollare a Spugna (MSK) riconosciuto per la prima volta a Padova, da Lenarduzzi nel 1939 grazie all’impiego dell’allora nuova tecnica dell’urografia e successivamente descritto nel 1949 da Cacchi e Ricci, rispettivamente urologo e patologo dell’Università patavina può essere annoverato tra le nefropatie congenite malformative per la presenza di ectasie precaliceali dei dotti collettori e per la sua frequente associazione con altre malformazioni congenite renali ed extrarenali. La funzione renale e la durata della vita nei pazienti MSK è normale; spesso si complica con lo sviluppo di nefrocalcinosi e nefrolitiasi. La patogenesi di MSK non è stata completamente chiarita ma la maggior parte degli autori concorda che si tratta di una patologia congenita con espressione ritardata. Che la causa di MSK potesse essere di natura genetica era suggerito dalla descrizione di alcuni casi familiari, dall’appartenenza di MSK al gruppo delle patologie malformative e dalla sua associazione con altre malattie ereditarie. La scoperta del gene/i responsabili della patologia è stato negli ultimi anni obiettivo del nostro gruppo di lavoro ed in particolare del mio lavoro di dottorato. L’ipotesi che ha dato inizio allo studio è che MSK sia la conseguenza di un disturbo durante lo sviluppo renale dell’interfaccia “gemma ureterale- mesenchima metanefrico” a causa di mutazioni/polimorfismi di RET, GDNF, o di altri geni coinvolti nell’embriogenesi renale, o in particolare a causa dell’interazione GDNF/RET. I risultati del sequenziamento diretto e test RFLP di GDNF su una casistica veneta di 112 pazienti, ben selezionata sulla base di stretti criteri urografici hanno permesso di identificare 1 variante rara della regione del promotore di GDNF (-27+18G>A) significativamente associata a MSK (p=0.02). Inoltre, la possibilità di estendere lo screening di GDNF su alcuni familiari di pazienti MSK ci ha permesso di scoprire che le varianti erano ereditate e che nelle famiglie erano associate al fenotipo MSK. Nella seconda parte del lavoro di dottorato è stata posta l’attenzione sui casi familiari di MSK. In collaborazione con la Clinica Nefrologica di Verona sono stati indagati 50 gruppi famigliari scelti random dalla coorte di 112 pazienti con MSK . Dall’’analisi mediante ecografia e/o Uro-TC estesa ai consanguinei della stessa generazione, e di 1, se possibile, 2 generazioni precedenti e/o successive è emerso che in 27 famiglie MSK segregava come carattere autosomico dominante, con espressività variabile e ridotta penetranza. Sui probandi di queste famiglie è stato fatto lo screening per il gene GDNF. Inoltre, in collaborazione con il laboratorio di Nefrologia Pediatrica dell’Università di Padova è stato fatto, lo screening di Six1, Spry1 e Pax2 che sono geni coinvolti nel processo di nefrogenesi renale e con un importante ruolo nei meccanismi di regolazione di GDNF, per un totale di 19 casi famigliari. Lo screening di GDNF mediante sequenziamento diretto delle regioni esoniche e delle giunzioni introne-esone non ha evidenziato nessuna variante rare né altre sostituzioni nucleotidiche. Allo stesso modo nessuna mutazione causativa è stata evidenziata per Six1, Spry1 e Pax2. Per Spry1 e Pax2 solo polimorfismi noti ma senza alcuna significatività statistica nelle frequenze alleliche confrontata con quella di popolazioni di controllo riportate in letteratura. Un altro obiettivo del mio lavoro di dottorato è stato quello di aver cercato di capire come varianti rare di GDNF possano essere associate al fenotipo MSK, in un sottogruppo di pazienti con nefrolitiasi, nefrocalcinosi ed MSK bilaterale. L’asportazione di un carcinoma renale in una paziente con MSK e mutazione di GDNF (-27+18G/C) ha dato l’opportunità di studiare per la mutazione di GDNF il suo significato funzionale e di verificare che cellule papillari renale prelevate da polo indenne al carcinoma renale e con bassi profili di espressione per GDNF, differenziavano spontaneamente verso un lineaggio osteogenico con la sintesi di proteine tipiche della matrice osteoide. Per cercare di approfondire se la down regolazione di GDNF, molto probabilmente dovuta alla mutazione che cade nella regione del promotore, possa avere avuto un coinvolgimento nel fenomeno di calcificazione osservato si è cercato di ottenere su cellule epiteliali renali (HK2), attraverso la tecnica di RNA interference, un silenziamento stabile di GDNF. I dati preliminari di questi ultimi esperimenti hanno mostrato che nelle cellule HK2 silenziate per GDNF vi era la presenza di depositi di Ca2PO4, confermati sia dalla colorazione von Kossa sia dall’analisi SEM. la presenza dei depositi di calcio fosfato non sono state osservate né nel controllo negativo né nei cloni silenziati in normali condizioni di coltura, mentre nel controllo negativo in condizione osteogenica i depositi erano presenti, seppur in minore quantità rispetto al clone silenziato. Sebbene preliminari, i nostri suggeriscono che la down regolazione di GDNF potrebbe favorire la deposizione di Ca2PO4 attraverso un meccanismo non ancora identificato. La nostra ipotesi è che l’apoptosi potrebbe essere la chiave.
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Knott, Laura. "Cooperation between GDNF/Ret and EphrinA/EphA4 signals for motor axon pathway selection in the limb." Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-78380.
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Wang, Ruizhong. "Therapeutic Effects of Neurotrophic Factors GDNF and Artemin on Experimental Neuropathic Pain and Dorsal Root Injury." Tucson, Arizona : University of Arizona, 2006. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1461%5F1%5Fm.pdf&type=application/pdf.
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Chen, Yan. "EFFECTS OF GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR (GDNF) ON STEM/PROGENITOR CELL PROLIFERATION AND DIFFERENTIATION." UKnowledge, 2005. http://uknowledge.uky.edu/gradschool_diss/233.
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Stem/progenitor cells are present in the adult brain; they undergo constantproliferation and differentiate into mature neurons in certain brain areas, a phenomenoncalled neurogenesis. This study investigated the effects of GDNF, a potent trophic factorof dopaminergic neurons, on neurogenesis in the brain. Nestin and 5-Bromo-2'-deoxyuridine (BrdU) were used as stem/progenitor cells markers.First, we observed extensive bilateral increases of stem/progenitor cells in thedentate gyrus and substantia nigra after continuous infusion of GDNF into the normal ratbrain. However, none of the BrdU+ cells showed neuronal features in the substantia nigraas characterized by immunocytochemical procedures. Next, we identified themorphology of BrdU+ cells after infusing the marker into the brain. While the proceduresincreased the BrdU labeling, neurogenesis was not observed in the basal ganglia. Underelectron microscope, the BrdU+ cells either were undifferentiated or showedcharacteristics of astrocytes. This observation is consistent with suggestions thatastrocytes serve as multipotent progenitors. Later, we repeated GDNF intrastriatalinfusion one month after a severe 6-hydroxydopamine (6-OHDA) lesion. The number ofBrdU+ cells was significantly higher in the GDNF recipients in the ipsilateral substantianigra and both sides of the dentate gyrus. However, no neurogenesis was observed. Inaddition, motor functions were not improved by GDNF treatment. Thus, we measured theeffects of GDNF administration directly into the substantia nigra six hours before apartial 6-OHDA lesion. HPLC measurements of dopamine and its metabolites showed asignificant increase of tissue level in the substantia nigra and striatum, respectively.Despite this, no newly generated dopaminergic neurons was detected in the basal ganglia.Taken together, our studies investigated the effects of GDNF on adultstem/progenitor cells in normal and lesioned rat brain. For the first time, we demonstratedthat GDNF promoted their proliferation in the dentate gyrus, suggesting it has a role inneurogenesis and the function of learning and memory. In each scenario, GDNFpromoted stem/progenitor cell proliferation, but failed to induce neurogenesis in thesubstantia nigra. We believed that the local microenvironment in the substantia nigra mayprevent the stem/progenitor cells to mature into functional neurons.
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FORREST, Shelley Lynne. "Effects of visceral inflammation and nerve injury on nociceptors expressing receptors for the GDNF family ligands." Thesis, The University of Sydney, 2013. http://hdl.handle.net/2123/9832.
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Members of the glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFL) comprising GDNF, neurturin and artemin, show efficacy in rat neuropathic pain models and promote regeneration after injury. Their receptors, GFRα1-3 respectively, are expressed by adult dorsal root ganglion neurons and have distinct central projections, suggesting different functions. This thesis used immunohistochemical techniques to investigate the impact of nerve injury and visceral inflammation on nociceptors expressing the GFRs in adult rats. Somatic and visceral nerve injury had profound effects on GFR-expressing neurons and their central terminals. Bladder afferent neurons expressing GFRs were characterised and effects of chronic bladder inflammation investigated. GDNF and artemin target different functional groups of bladder afferent neurons, potentially regulating different components of bladder function but were unaffected by inflammation. A population of bladder neurons undergoing structural remodelling during inflammation was identified. The final study demonstrated that GFRα3 labels specific populations of afferent axons, sympathetic noradrenergic vasoconstrictor axons and glia in the bladder. Results from this thesis indicate GFLs and their receptors represent promising targets for therapies aimed at regeneration and development of pain. Visceral and somatic afferents may have different growth factor sensitivities that may impact the degree of regeneration or development of sensitization.
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Schindler, Cora [Verfasser], Astrid [Akademischer Betreuer] Weyerbrock, and Nadja [Akademischer Betreuer] Osterberg. "GDNF moduliert die Sensitivität humaner Glioblastoma multiforme Zellen gegenüber dem Stickstoffmonoxid-Donor JS-K in vitro." Freiburg : Universität, 2018. http://d-nb.info/1153335530/34.
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Wang, Ruizhong. "Therapeutic Effects of Neurotrophic Factors GDNF and Artemin on Experimental Neuropathic Pain and Dorsal Root Injury." Diss., The University of Arizona, 2005. http://hdl.handle.net/10150/195103.
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Glial cell line derived neurotrophic factor (GDNF) and artemin maintain the structural and functional integrity of the adult nervous system and regulate the plasticity of the injured or diseased adult nervous system apparently by interacting with GFRalpha1/RET and GFRalpha3/RET systems.The clinical management of neuropathic pain is particularly challenging. Current therapies for neuropathic pain modulate nerve impulse propagation or synaptic transmission; these therapies provide limited efficacy due in part to dose-limiting and undesirable side effects. Here we show that chronic infusion of GDNF normalizes nerve injury-induced neurochemical changes and prevents the expression of neuropathic pain. Systemic artemin produces partial to complete normalization of multiple morphological and neurochemical features of the injury state.Damaged axons in the dorsal root of adult mammals rarely regrow into the spinal cord, leading to the permanent loss of sensory function. This continues to be a major unmet clinical challenge relevant to a host of disease and trauma-induced injuries to peripheral nerves. Here we show that systemic artemin restores sensory function, apparently permanently, in an experimental dorsal root injury model in rats, including responses to noxious heat, mechanical and chemical stimuli and sensory input-required proprioceptive responses of placement stabilization, targeting and grasping. These effects are likely to result from successful support of multiple classes of sensory afferents which cross the dorsal root entry zone into the spinal cord and make functional connections with spinal neurons. Delayed artemin treatment defines the "therapeutic window" for artemin application following injury to the nerve roots, indicating that this strategy may ultimately be of clinical benefit.Our results indicate that the behavioral symptoms of neuropathic pain states can be treated successfully, and that partial to complete reversal of associated morphological and neurochemical changes can be achieved with artemin. The damaged axons can re-grow perhaps into their original region of occupation, and make functional connections with spinal neurons, resulting in apparently permanent restoration of the lost sensory function following dorsal root injury. Our present studies provide experimental evidence that the neurotrophic factors GDNF and artemin may serve as clinically viable drugs in treating peripheral nerve injury or other neurodegenerative diseases.
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Klein, Pontus [Verfasser], and Rüdiger [Akademischer Betreuer] Klein. "Functions of GDNF/Ret signaling in models of autosomal recessive Parkinson’s disease / Pontus Klein. Betreuer: Rüdiger Klein." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2011. http://d-nb.info/1048014614/34.
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Rémy, Sévérine. "Les neurones dopaminergiques : le gdnf et la neurturine comme facteurs de survie la xenotransplantation comme approche restauratrice." Nantes, 2001. http://www.theses.fr/2001NANT2020.
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La maladie de parkinson se caracterise par une perte progressive des neurones dopaminergiques. Deux approches complementaires peuvent etre envisagees comme strategie therapeutique : l'apport de facteurs neurotrophiques prevenant la mort neuronale ou la greffe de neurones permettant de restaurer la population neuronale perdue. Une partie de mon travail de these a donc consiste a etudier la regulation du glial cell line-derived neurotrophic factor (gdnf), de la neurturine (ntn) et de leurs recepteurs, qui favorisent la survie des neurones dopaminergiques. Les resultats suggerent un role de ces facteurs en cas d'inflammation dans le snc. En effet, le traitement de cultures primaires de cellules gliales par du lps entraine une augmentation des transcrits du gdnf et l'addition de tnf stimule l'expression de la ntn. De plus, la diminution des niveaux du recepteur gfr1 apres traitement par du lps ou du tnf suggere un role particulier de ce recepteur dans les cellules gliales. Par ailleurs, mon travail montre que l'expression du gdnf et de ses recepteurs peut etre controlee par des voies de signalisation communes. Toutefois, l'effet stimulateur de l'hormone thyroidienne sur l'expression de gfr2, suggere des voies de regulation propres. La seconde partie de mon travail a consiste a etudier une problematique importante pour le developpement de la greffe comme approche therapeutique : le rejet. Pour comprendre les mecanismes mis en cause, nous avons compare la reaction immunitaire suite a la greffe de neurones ftaux porcins qui n'expriment pas de facon constitutive les molecules du cmh a celle de cellules endotheliales aortiques de porc. Ces dernieres ont ete rapidement rejetees avec une implication majeure des macrophages et des polymorphonucleaires,
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Jezierski, Anna. "Characterization and Therapeutic Potential of Human Amniotic Fluid Cells in Mediating Neuroprotection." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/26157.
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Brain injury, either surgically induced or as a result of trauma or stroke, is one of the leading causes of death and disability worldwide. Since transplantable stem cell sources are showing a great deal of promise and are actively being pursued to provide neuroprotection post-injury, in this body of work, we set out to characterize and examine the therapeutic potential of amniotic fluid derived (AF) cells as a potential cell source for cell-based therapies in mediating neuroprotection post-injury. Despite their heterogeneity, we found that AF cells are mainly epithelial in origin and express various genes involved in stem cell maintenance and neural commitment. A very small subset of AF cells also express pluripotency markers OCT4a, SOX2 and NANOG, which can be enriched for by single cell cloning. SOX2 positive clones have the capacity to give rise to a neuronal phenotype, in neural induction conditions, which can be used to examine the neural differentiation capabilities of AF cells. Subsequently, we examined the ability of AF cells to mediate a neuroprotective effect in a surgically induced brain injury model through gap junctional-mediated direct cell-cell communication and as a vehicle for GDNF delivery post-injury. AF cells express high levels of CX43 and are able to establish functional gap junctional intercellular communication (GJIC) with cortical astrocytes. We report an induction of Cx43 expression in astrocytes following injury and demonstrate, for the first time, CX43 expression at the interface between implanted AF cells and host astrocytes. In an effort to boost host endogenous neuroprotective mechanisms post-injury, via neurotrophic factor delivery, we engineered AF cells to secrete GDNF (AF-GDNF). GDNF pre-treatment significantly increased AF cell and cortical neuron survival rates following exposure to hydrogen peroxide. AF-GDNF cells, seeded on polyglycolic acid (PGA) scaffolds, survived longer in serum-free conditions and continued to secrete GDNF post-implantation activating the MAPK/ERK signaling pathway in host neural cells in the peri-lesion area. Despite some promising trends, we did not observe significant behavioural improvements following AF-GDNF/PGA implantation nor reduced lesion volume during the 7 day time-frame. In conclusion, through GJIC with cortical astrocytes and delivery of exogenous neurotrophic factors, AF cells hold great promise in mediating neuroprotection post-injury.
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Brizard, Mara. "Stratégies de transfert du gène codant le GDNF en vue d'une thérapie génique de la maladie de Parkinson." Paris 5, 2004. http://www.theses.fr/2004PA05N083.
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Le transfert du gène codant le facteur neurotrophique dérivé des cellules gliales (GDNF) permet de protéger voire de restaurer les neurones dopaminergiques nigrostriés qui dégénèrent dans la maladie de Parkinson (MP). Afin d'améliorer les systèmes de transfert de gènes, nous avons voulu développer des vecteurs adénoviraux "gutless". Les résultats limités de production nous ont toutefois conduit à recourir aux vecteurs lentiviraux. Nous avons alors montré que des vecteurs lentiviraux pseudotypés avec deux enveloppes virales différentes permettent un transfert de gène efficace et durable dans le cerveau murin et peuvent être injectés plusieurs fois , même en présence de taux élevés d'anticorps neutralisants dirigés contre la protéine d'enveloppe. Enfin, nous avons montré que, dans un modèle expérimental de phase précoce de la MP, l'administrationGlial cell line-derived neurotrophic factor (GDNF) gene transfer has protective and survival-promoting effects on nigrostriatal dopamine neurons which degenerate in the Parkinson's disease (PD). In order to improve gene transfer systems, we developed "gutless" adenoviral vectors. Their production proved inadequate, what led us to opt for lentiviral vectors. We then showed that lentiviral vectors pseudotyped with two different viral envelopes allow an efficient and sustained gene transfer in mouse brain. Moreover, they can be administered successfully several times, even with high titers of neutralizing antibodies directed against the pseudotyping envelope protein. We finally found that reproduces the early stage of PD, lentivirus-mediated intrastriatal GDNF delivery can promote reinnervation of the partially deafferated striatum accompanied by functional recovery
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Barbosa, Izabela Guimaraes. "Estudo da concentração plasmática de fatores neurotróficos (BDNF,NGF e GDNF) em pacientes com transtorno bipolar do humor." Universidade Federal de Minas Gerais, 2009. http://hdl.handle.net/1843/BUBD-8AEM62.
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Introduction: Bipolar disorder (BD) is a prevalent and chronic illness associated with substantial morbidity. There is a growing body of evidence indicating that alterations in neurotrophic factors, mainly in brain-derived neurotrophic factor (BDNF), may play a role in the pathophysiology of BD. Objective The aim of this study was to examine neurotrophic factors plasma levels (BDNF, NGF and GDNF) in BD patients, type I, compared with drug-free healthy controls and theirrelationship with comorbitidies and medications in use. Methods: We measured plasma neurotrophic factor (BDNF, NGF e GDNF) concentration by an enzyme linked immunosorbent assay methods in 74 subjects, including 21 drug-free healthy controls, 53 patients with bipolar disorder, type I (19 euthymic patients and 34 in current maniacepisode). At the time of the study, no one the subjects were in treatment with corticosteroids, antibiotics or anti-inflammatory for at least four weeks. Results: Compared to healthy controls, plasma concentrations GDNF (p=0,395) and NGF (p=0,795) theres no significant difference in the patients group. Plasma BDNF concentrations, compared to healthy controls, were significantly increased in patients with mania and euthymia (p=0,001) with no significant difference among them. Drug treatments, comorbid psychiatric disorders, clinical disorders, age, years of study, maniac symptoms or psychosis had no effect on elevated circulating BDNF in affective patients. BDNF was elevated only in those patients in bipolar disorder whose first episode of humor was at least 10 years previous at the study (p=0,049). Conclusions: Present results demonstrated reduced circulation plasma BDNF levels in patientswith BD, for the first time, mainlining in patients with longer than 10 years since the first episode of humor. Our findings suggest the role of BDNF in the pathophysiology of BD, like other findings in literature.Introdução: O transtorno bipolar do humor (TBH) é uma síndrome psiquiátrica de prevalência elevada, curso crônico, associada com grande morbidade. Evidências na literatura sugerem quealterações nos fatores neurotróficos, principalmente fator neurotrófico derivado do cérebro (BDNF), tem um importante papel na fisiopatologia do TBH. Objetivo: O objetivo deste estudo é avaliar a concentração plasmática dos níveis de fatores neurotróficos (BDNF, NGF e GDNF) em pacientes com TBH tipo I, comparando-os com controles saudáveis e correlacionando com a presença de comorbidades e medicações em uso. Métodos: Foram realizados análises das concentrações plasmáticas de fatores neurotróficos (BDNF, NGF e GDNF), através do método de ELISA, em 74 sujeitos, incluindo 21 controlessaudáveis e 53 pacientes bipolares (34 pacientes em mania e 19 pacientes em eutimia). No momento da entrada no estudo nenhum dos sujeitos estava em uso de corticosteróides, antibióticos ou antiinflamatórios pelo menos há 4 semanas. Resultados: Comparado com controles saudáveis, as concentrações plasmáticas de GDNF(p=0,395) e NGF (p=0,795) não diferenciaram do grupo controle. As concentrações plasmáticas de BDNF, comparado com o grupo controle, foram significativamente elevadas nos pacientes, tanto em episódios maníacos quanto em eutimia (p=0,001). Elevações nos níveis circulantes de BDNF não foram associadas com tratamento medicamentoso, comorbidades psiquiátricas, comorbidades clínicas, idade, escolaridade, intensidade de sintomas maníacos ou presença depsicose. Pacientes que apresentaram o primeiro episodio de humor há pelo menos 10 anos, mostraram elevações mais significativas nos níveis plasmáticos de BDNF (p=0,049). Conclusões: Observamos, pela primeira vez, elevações nos níveis plasmáticos de BDNF empacientes com TBH tipo I, especialmente nos com evolução de doença superior a 10 anos. Nossos achados corroboram dados da literatura que sugerem papel do BDNF na fisiopatologia do TBH.
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Kelps, Kristen. "Molecular and Cellular Characterization of Dopamine Neuron Stimulating Peptides." UKnowledge, 2013. http://uknowledge.uky.edu/neurobio_etds/6.
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Parkinson’s disease, the second most common neurodegenerative disease, is characterized by the loss of dopaminergic neurons within the substantia nigra. Currently, the treatments available for PD are symptomatic treatments that do not stop the progression of the disease. Trophic molecules, such as glial cell-line derived neurotrophic factor (GDNF), have been evaluated as potential therapeutic molecules that could stop the loss of neurons and potentially restore some of the neurons that have already been lost. However, these trophic molecules are large making them difficult to produce and delivery. Here we characterize three peptides (DNSP-5, DNSP-11, and DNSP-17) to determine it they are stable and offer protective effects similar to GNDF allowing them to be potential therapeutic molecules.
The data presented here involves the evaluation of the molecular and cellular mechanism of DNSP-5, DNSP-11, and DNSP-17, which are derived from prosequence of GDNF. Initial studies were carried out to evaluate the physical characteristics of these three peptides to determine their viability as potential therapeutic molecules. The structure and stability of these peptides were evaluated. Based on the data it was determined that the three peptides do not interact in vitro, allowing for further individual evaluations of the peptides. It was also determined that the peptides were stable when stored at both -80°C and 37°C for one month, allowing them to both potentially be stored during treatment.
Cell culture assays and proteomic profiling were utilized to determine binding partners and potential mechanisms through which DNSP-11 may be able to mediate apoptosis. It was determined that DNSP-11 was able to interact with a variety of binding partners that are involved in metabolism. These studies have aided in the understanding of neurotrophic factor prosequence function, but will also serve as a starting point for the development of novel trophic factors for PD treatment.
Finally, the interaction between DNSP-11 and GAPDH was evaluated as a potential anti-apoptotic mechanism. GAPDH has previously shown to play a role in mediating apoptotic pathways. It was hypothesized that the observed interaction between DNSP-11 and GAPDH could mediate that role of GAPDH in apoptosis and afford DNSP-11 its observed anti-apoptotic effects. It was observed that while DNSP-11’s interaction with GAPDH may play a role in its anti-apoptotic effects, it does not appear to be the only mechanism involved. Based on this data, it is likely that the other metabolic binding partners play a role in DNSP-11’s anti-apoptotic mechanisms and therefore, these interactions should be further evaluated.
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Mahesh, Gajanan Sahare. "Establishment of Long-Term Culture and Elucidation of Self-Renewal Mechanisms of Primitive Male Germ Cells in Cattle." Kyoto University, 2015. http://hdl.handle.net/2433/200509.
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Kyoto University (京都大学)0048
新制・課程博士
博士(農学)
甲第19243号
農博第2140号
新制||農||1036(附属図書館)
学位論文||H27||N4947(農学部図書室)
32242
京都大学大学院農学研究科応用生物科学専攻
(主査)教授 今井 裕, 教授 祝前 博明, 教授 松井 徹
学位規則第4条第1項該当
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Nidadavolu, Prakash [Verfasser]. "Parkin cooperates with GDNF/Ret signaling during the development and maintenance of the dopaminergic system in mice / Prakash Nidadavolu." Hamburg : Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky, 2017. http://d-nb.info/1234658348/34.
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Buj-Bello, Anna. "Neurotrophic actions of GDNF and neurturin in the developing avian nervous system and cloning and expression of their receptors." Thesis, University of St Andrews, 1997. http://hdl.handle.net/10023/14781.
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The main aim of this project was to determine the neurotrophic actions of glial cell line-derived neurotrophic factor (GDNF) and neurturin, two novel members of the transforming growth factor-beta superfamily of proteins, on neurons from the peripheral nervous system and to identify their receptors. It is found that GDNF promotes the survival of multiple populations of chicken sensory and autonomic neurons in culture throughout development. Whereas sympathetic, parasympathetic and propioceptive neurons become less responsive to GDNF with age, enteroceptive and sensory cutaneous neurons become more responsive to GDNF. GDNF mRNA is expressed in the tissues innervated by these neurons, and developmental changes in its expression in several tissues mirror the changing responses of the innervating neurons to GDNF. These results have changed the previous notion that GDNF is a highly specific neurotrophic factor for motoneurons and dopaminergic neurons. It is shown that neurturin, which is structurally related to GDNF, also promotes the in vitro survival of embryonic chicken sensory and autonomic neurons. Thus, GDNF and neurturin compose a novel subfamily of homologous neurotrophic factors with a similar pattern of activity. The cloning of chicken GDNF receptor-α (GDNFR-α) and a novel receptor termed neurturin receptor-α (NTNR-α) is reported. GDNFR-α and NTNR-α are homologous receptors linked to the membrane via a glycosyl- phosphatidylinositol linkage. It is shown that ectopic co-expression in neurons of GDNFR-α with RET (rearranged during transfection), a transmembrane receptor tyrosine kinase, confers a survival response to GDNF, but not neurturin, and that co-expression of NTNR-α with RET confers a survival response to neurturin, but not GDNF. GDNFR-α and NTNR-α mRNAs are widely expressed in the nervous system, including GDNF and neurturin responsive neurons, and in non-neuronal tissues. These findings indicate that GDNF and neurturin promote neuronal survival by signalling via similar multicomponent receptors that consist of a common transducing receptor tyrosine kinase and a member of a newly emerging family of glycosyl-phosphatidylinositol-linked receptors that confer ligand- specificity.
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Mammeri, Hamid. "CIBLAGE ASTROCYTAIRE DE L'EXPRESSION DU GDNF PAR DES LENTIVECTEURS POUR UNE THERAPIE GENIQUE DE PROTECTION DE LA MALADIE DE PARKINSON." Phd thesis, Université Pierre et Marie Curie - Paris VI, 2006. http://tel.archives-ouvertes.fr/tel-00184121.
Full textAbstract:
La maladie de Parkinson est une maladie neurodégénérative caractérisée par la mort progressive des neurones dopaminergiques de la substance noire (SN). Cette mort neuronale entraîne un déficit en dopamine (DA) dans le striatum, responsable de la survenue des symptômes. Dans la perspective d'un traitement visant à protéger les neurones de la SN, de nombreuses études ont été centrées sur l'utilisation du glial cell-line derived neurotrophic factor (GDNF), facteur neurotrophique et neuroprotecteur des neurones dopaminergiques. Son efficacité thérapeutique a été démontrée par de nombreuses études dans des modèles animaux de la MP et lors d'essais cliniques.
Depuis une dizaine d'années, de nombreux travaux ont démontré l'efficacité de la thérapie génique (TG) comme méthode d'administration du GDNF et un effort particulier est entrepris pour optimiser cette approche. Cependant, malgré des résultats très encourageants obtenus dans les modèles murins et de primates de la MP, il s'est révélé que l'utilisation des vecteurs viraux se confrontait à une limite majeure. En effet, le ciblage préférentiellement neuronal de ces vecteurs entraîne la dispersion de la protéine dans la voie striatonigrale provoquant ainsi la formation massive de collatérales dans des zones non désirées.
Afin d'éviter la dispersion du GDNF, nous avons étudié la restriction de sa localisation au striatum en ciblant préférentiellement les astrocytes striataux via un vecteur lentiviral.
Une première partie du travail porte sur la caractérisation d'un vecteur pseudotypé par l'enveloppe Mokola. Chez la souris, l'enveloppe permet un ciblage spécifique des astrocytes quel que soit le promoteur utilisé, contrairement aux rat et primate, chez lesquels un ciblage préférentiellement astrocytaire est obtenu en combinaison avec le promoteur CMV.
Dans une seconde partie, le vecteur pseudotypé par Mokola a été utilisé pour étudier l'effet d'une expression restreinte de GDNF aux astrocytes striataux sur la protection de la voie nigrostriée. L'injection d'un vecteur permettant la synthèse de GDNF (Mok-GDNF) dans un modèle de rat de la MP permet une forte et stable synthèse de GDNF pendant au moins un an. Bien que le GDNF soit très majoritairement retrouvé au niveau du striatum et du globus pallidus, un très faible transport du GDNF dans les zones de projection est détecté. Cette dispersion résiduelle ne permet pas la génération de collatérales ectopiques. L'injection du vecteur Mok-GDNF permet une protection du système dopaminergique de la voie nigrostriée ainsi que le rétablissement d'un turn-over de la DA normal, traduit par une restauration complète du comportement moteur. Ces résultats indiquent que l'utilisation du vecteur pseudotypé par Mokola pour exprimer le GDNF se révèle optimale pour la TG de protection de la MP.
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Stark, Robert Stefan [Verfasser], and Johanna [Akademischer Betreuer] Anneser. "Genetisch modifizierte Knochenmarkstammzellen als Therapieansatz bei Amyotropher Lateralsklerose : lentivirale Transduktion von GDNF und BDNF / Robert Stefan Stark. Betreuer: Johanna Anneser." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/1047762072/34.
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Meka, V. V. Durga Praveen [Verfasser], and Edgar [Akademischer Betreuer] Kramer. "Parkin cooperates with GDNF/Ret signaling to prevent dopaminergic neurodegeneration in mice / V. V. Durga Praveen Meka ; Betreuer: Edgar Kramer." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2017. http://d-nb.info/1144485592/34.
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Dolatshad, Nazanin Fatima. "Expression analysis of GDNF family of neurotrophic factors and their receptors in the postnatal, adult and ageing gut and bladder of rats." Thesis, Open University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288967.
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Chi, L. (Lijun). "Sprouty and Cerberus proteins in urogenital system development." Doctoral thesis, University of Oulu, 2007. http://urn.fi/urn:isbn:9789514284540.
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Abstract
The embryonic urogenital system (UGS) generates the metanephric kidney, gonad and the adrenal gland. It is well known that the development of the UGS is regulated by sequential and reciprocal epithelial and mesenchymal tissue interactions but the secreted mediators involved are still poorly known. The action of such inductive signals is typically regulated by specific antagonists. The Sprouty (Spry) proteins compose one family of cytoplasmic regulators that typically repress the function of the receptor tyrosine kinase (RTK) signal transduction pathways. The DAN/Cerberus (Cer) family that encodes secreted proteins bind and antagonize the Bmp, Wnt and Nodal signals. In this study the roles of Spry and Cer1 was addressed during mouse UGS development by targeted expression of SPROUTY2 (SPRY2) and Cer1 in the ureteric bud and Wolffian duct under the Pax2 promoter. Changes induced in the UGS assembly process were analyzed in detail to reveal the normal developmental roles of these proteins.
SPRY2 expression led to either complete lack of the kidney, reduction in the kidney size or formation of unilateral kidney with reduced size. The SPRY2 mediated reduction in kidney size was accompanied by inhibition of expression of genes that are known to regulate kidney development. The results indicated that the Spry may take part in kidney development by coordinating the reciprocal cell signaling between the ureteric bud, the mesenchymal cells and stromal cells.
In addition to the kidney, the gain of SPRY2 function revealed an important role in the control of male gonadogenesis. SPRY2 over expression in the Wolffian duct malformed the Wolffian duct derivatives, diminished the number of seminiferous tubules and the amount of the interstitial tissue associated with reduced mesonephric cell migration to the testis. Exogenous FGF9 rescued mesonephric cell migration inhibited by SPRY2. It was concluded that Spry protein contribute to male sexual organogenesis by antagonizing Fgf9 signaling.
When the Cer1 gene was over expressed in the ureteric bud this lead unexpectedly to increased kidney size. The Cer1 mediated promotion of kidney size was demonstrated to involve enhanced ureteric bud morphogenesis. At the molecular level Cer1 protein function lead to inhibition of Bmp4 gene expression and concurrent upregulation of Gdnf and Wnt11 expression. Notably, excess BMP4 reduced the Cer1 stimulated ureteric bud branching and downregulated normally expression of Gdnf and Wnt11 in the embryonic kidney. Based on the presented data it is proposed that the establishment of mammalian organ size is under the control of both systemic and the intrinsic factors.
Together the work demonstrates significant roles for the proteins that typically inhibit growth factor signaling or signal transduction. Hence organogenesis is controlled by coordination between positive and negative growth factor regulator signals.
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Goodison, Tavia. "Capacity of Neurotrophic Factors of the GDNF Family in Supporting the Survival of Dopaminergic Neurons in the Central Nervous System of the Aging Mouse." Thesis, Griffith University, 2013. http://hdl.handle.net/10072/367684.
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Dopaminergic neurons of the substantia nigra are vital for proper motor function. The Glial cell line-derived neurotrophic factor (GDNF) family of neurotrophic factors have been shown to promote the survival of dopaminergic neurons both in vitro and in vivo. GDNF and its related factor neurturin have both been trialled as a therapy for Parkinson’s patients for which degeneration of dopaminergic neurons is hallmark pathology. However, GDNF and neurturin are not required for proper development of dopaminergic neurons. Knockout of the GDNF gene in mice causes improper formation of the enteric nervous and kidneys causing death shortly after birth but does not cause any changes in dopaminergic phenotype. Knockout of the neurturin gene is non-lethal but causes abnormalities in enteric, parasympathetic and sensory neurons. No abnormalities in the brain of neurturin knockout have been reported however very little work has been done in this area. It appears that these two neurotrophic factors are not required for successful dopaminergic development.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Griffith University School of Biomolecular and Physical Sciences
Science, Environment, Engineering and Technology
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Brown, Russell W., Seth L. Kirby, Adam R. Denton, John M. Dose, Elizabeth D. Cummins, Wesley Drew Gill, and Katherine C. Burgess. "An Analysis of the Rewarding and Aversive Associative Properties of Nicotine in the Neonatal Quinpirole Model: Effects on Glial Cell Line-Derived Neurotrophic Factor (GDNF)." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/940.
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This study analyzed the associative properties of nicotine in a conditioned place preference (CPP) paradigm in adolescent rats neonatally treated with quinpirole (NQ) or saline (NS). NQ produces dopamine D2 receptor supersensitivity that persists throughout the animal's lifetime, and therefore has relevance towards schizophrenia. In two experiments, rats were ip administered quinpirole (1mg/kg) or saline from postnatal day (P)1–21. After an initial preference test at P42–43, animals were conditioned for eight consecutive days with saline or nicotine (0.6mg/kg free base) in Experiment 1 or saline or nicotine (1.8mg/kg free base) in Experiment 2. In addition, there were NQ and NS groups in each experiment given the antipsychotic haloperidol (0.05mg/kg) or clozapine (2.5mg/kg) before nicotine conditioning. A drug free post-conditioning test was administered at P52. At P53, the nucleus accumbens (NAc) was analyzed for glial cell-line derived neurotrophic factor (GDNF). Results revealed that NQ enhanced nicotine CPP, but blunted the aversive properties of nicotine. Haloperidol was more effective than clozapine at blocking nicotine CPP in Experiment 1, but neither antipsychotic affected nicotine conditioned place aversion in Experiment 2. NQ increased accumbal GDNF which was sensitized in NQ rats conditioned to nicotine in Experiment 1, but the aversive dose of nicotine reduced GDNF in NQ animals in Experiment 2. Both antipsychotics in combination with the aversive dose of nicotine decreased accumbal GDNF. In sum, increased D2 receptor sensitivity influenced the associative properties and GDNF response to nicotine which has implications towards pharmacological targets for smoking cessation in schizophrenia.