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1
Gilks, C. F. "The surface of Plasmodium chabaudi infected erythrocytes." Thesis, University of Oxford, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233501.
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Watkins, Katherine Ruth. "Investigation of pre-erythrocytic malaria vaccines in a mouse model using transgenic parasites." Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534200.
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Achtman, Ariel H. "The B cell response to Plasmodium chabaudi chabaudi : malaria in the mouse model." Thesis, Open University, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398011.
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Min-Oo, Gundula Ellen. "The genetic basis of malaria susceptibility: uncovering novel host factors in a mouse model of blood-stage infection." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=66739.
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This thesis examines the genetic factors controlling host response to malaria. Recombinant congenic strains AcB55 and AcB61 were identified as uniquely resistant to malaria despite a susceptible genetic background. These mice display splenomegaly, anemia, reticulocytosis and extra-medullary erythropoiesis. Genome wide mapping led to the identification of a mutation in pyruvate kinase (PklrI90N) that is associated with increased survival and decreased peak parasite levels. We found a significant malaria-protective effect with a second Pklr mutation (PklrG338D) on a distinct genetic background (CBA/N), thus validating our initial findings. The mechanism of protection was linked to increased erythrocyte uptake and compensatory erythropoiesis. Subsequently, we showed that PK-deficiency in humans was protective against P.falciparum replication in vitro. A second genetic locus in AcB55, Char9, was identified and localized to a 14Mb C57Bl/6-derived congenic segment. The Vnn1/Vnn3 genes map within the minimal interval and encode a pantetheinase enzyme; they show cis-regulated gene expression A/J-like alleles associated with an absence of mRNA. In addition, no enzymatic activity was detected in A/J tissues. Administration of cysteamine, the product of pantetheinase, to susceptible A/J mice resulted in increased survival and decreased parasite levels. The inhibition of parasite replication by cysteamine suggests a potential for this compound to be used as a novel anti-malarial monotherapy or in combination with current therapeutics. Finally, a third recombinant congenic strain, AcB62, shows rapid parasite replication with an early peak of infection, despite the presence of the PklrI90N mutation. AcB62 mice do display PK-deficiency associated anemia, erythropoiesis, tissue iron overload, and concomitant increases in iron-regulated proteins. We identified a novel locus controlling peak parasite levels in an [AcB6<br>Cette thèse examine les facteurs génétiques contrôlant la réponse de l'hôte au paludisme. Les souches recombinantes congéniques (RCS) AcB55 et AcB61 ont été identifiées comme présentant une résistance unique au paludisme malgré un fond génétique de susceptibilité. Ces souris développent une splénomégalie, de l'anémie, de la réticulose et une érythropoïèse extra médullaire. Un génome scan a conduit à l'identification d'une mutation de la pyruvate kinase (PklrI90N), laquelle est associée à une survie accrue et à une diminution des niveaux de pic de parasitémie. Un effet protecteur significatif contre le paludisme, du à une seconde mutation de la pyruvate kinase (PklrG338D) sur un fond génétique différent (CBA/N), a également été mis en évidence, validant ainsi nos premiers résultats. Le mécanisme de protection est associé à une augmentation de la phagocytose érythrocytaire et de l'érythropoïèse compensatoire. Nous avons également montré, chez l'humain, qu'un déficit en pyruvate kinase protégeait contre la réplication de P. falciparum in vitro. Un second locus, Char9, a été identifié sur la RCS AcB55 et a été localisé sur un segment congénique de 14Mb dérivé de C57Bl/6. Les gènes Vnn1/Vnn3 sont situés à l'intérieur de l'intervalle minimum et codent pour une enzyme pantéthéinase. Leur expression est régulée en cis et les allèles de type A/J ne codent pour aucun ARNm. Par ailleurs, aucune activité enzymatique n'a été détectée dans les tissus A/J. L'administration de cystéamine (un produit de la pantéthéinase) à des souris susceptibles A/J est responsable d'une survie accrue et d'une diminution des niveaux de parasitémie. L'inhibition de la réplication du parasite par la cystéamine suggère que ce composé pourrait potentiellement être utilisé comme nouvel antipaludéen, en monothérapie ou en combinaison avec des drogues actue
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Wyse, Ana Paula Pintado. "Optimal control for malaria vector for a seasonal mathematical model." Laboratório Nacional de Computação Científica, 2007. http://www.lncc.br/tdmc/tde_busca/arquivo.php?codArquivo=140.
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In the Amazonian region occurs a variation in the malaria incidence, which is related to the pluviometric variation annual. The mathematical model proposed here considers this seasonality and different treatment intensities accessible to the infected people. The numerical evidence the seasonal fluctuation and the relationship between the environment temperature and treatment efficiency, showing that the temperature increase strongly affects the extrinsic latent period,reducing the healthy care efficiency. Because malaria treatment already exists it should be import. For another hand, even the investment in treatment is an efficient form to block the epidemy, it is not always sufficient, because the protozoan has been more resistent to the medicine; then scientists are creating transgenic mosquitoes refractory to malaria to couple with wild one, generating descending transgenic. To avaliate this situation, we consider here a mathematical model that describes the relatioship between these populations. Then, we formulate and solve an optimal control problem indicating how the transgenic mosquitoes should be introduced in the environment. The numerical simulations show the effectiveness of the control.<br>Na Amazônia ocorre uma variação na incidência de malária que está intimamente relacionada à variação pluviométrica ao longo do ano. O modelo matemático aqui proposto considera esta sazonalidade e diferentes intensidades de tratamento acessíveis às pessoas infectadas. Experimentos numéricos descrevem a flutuação sazonal e evidenciam uma relação inversa entre a temperatura e eficiência do tratamento, mostrando que um aumento na temperatura afeta fortemente o período latente extrínseco, reduzindo a eficiência do investimento em saúde. Como o tratamento para os infectados existe, é importante concentrar esforços nesse sentido para obter sucesso no controle da malária. Por outro lado, embora o investimento em tratamento seja uma forma eficaz de impedir a epidemia, isso nem sempre é suficiente, pois é fato que o protozoário tem se mostrado cada vez mais resistente aos medicamentos; por esse motivo, cientistas estão criando mosquitos transgênicos refratários à malária que devem acasalar com os mosquitos selvagens, gerando descendência transgência. Para avaliar esta situação, consideramos neste trabalho um modelo matemático que descreve de maneira simplificada a relação entre estas duas populações. A partir desse modelo, formulamos e resolvemos um problema de controle ótimo indicando uma forma adequada de introduzir esses mosquitos transgênicos. Experimentos numéricos mostram a eficácia do controle adotado.
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Komuro, Yutaro. "Altered adult neurogenesis in a mouse model of human tauopathy." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1434743393.
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Ohashi, Taryn M. "Eradicating Malaria: Improving a Multiple-Timestep Optimization Model of Malarial Intervention Policy." Scholarship @ Claremont, 2013. http://scholarship.claremont.edu/scripps_theses/273.
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Malaria is a preventable and treatable blood-borne disease whose complications can be fatal. Although many interventions exist in order to reduce the impacts of malaria, the optimal method of distributing these interventions in a geographical area with limited resources must be determined. This thesis refines a model that uses an integer linear program and a compartmental model of epidemiology called an SIR model of ordinary differential equations. The objective of the model is to find an intervention strategy over multiple time steps and multiple geographic regions that minimizes the number of days people spend infected with malaria. In this paper, we refine the resolution of the model and conduct sensitivity analysis on its parameter values.
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Huan, Xiang Quan. "Depot cytokines and chemokines for antitumor therapy in a mouse model /." [St. Lucia, Qld.], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18435.pdf.
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Krishnamurthy, Varun K. "Biomechanical and Molecular Approaches to Aortic Valve Disease in a Mouse Model." University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1354297165.
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Quiggle, David Douglas. "The effects of R-flurbiprofen in reducing tumors in a multiple intestinal neoplasia mouse model." CSUSB ScholarWorks, 2001. https://scholarworks.lib.csusb.edu/etd-project/2009.
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The design of the proposed study was to administer R-FB to 72-day old Min/+ mice for up to 42 days. In order to capture the process of tumor reduction, animals were necropsied at various time points. At each time point animals were evaluated for tumor loads and presence of apoptotic cells along the small intestine. Studies have shown that when R-flurbiprofen (R-FB) is administered in the Min/+ mouse model it can cause the prevention and regression on intestinal tumors.
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Habli, Mounira A. M. D. "Recapitulation of Human Placental Insufficiency in a Novel Mouse Model :New Paradigm in Translational Research." University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1338582019.
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Birget, Philip Laurent Guillaume. "Evolutionary ecology of parasites : life-history traits, phenotypic plasticity, and reproductive strategies." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/28805.
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Adaptive phenotypic plasticity, the ability of a genotype to give rise to different phenotypes in different environments, evolves to allow organisms to fine-tune their life-history traits according to the varying conditions they encounter during their lives. Reproductive investment - the manner in which organisms divide their resources between survival and reproduction - is well studied in evolutionary ecology because it is a key determinant of fitness. However, whilst plasticity in reproductive effort is well understood for free-living multicellular taxa (such as insects, birds, and mammals), the application of evolutionary theory for plasticity and life history strategies to unicellular parasites and pathogens is lacking. In this thesis, I use empirical and theoretical approaches to uncover how differential resource allocation to non-replicating, sexual stages (gametocytes) versus asexually replicating stages can be harnessed by the rodent malaria parasite Plasmodium chabaudi to maximise its fitness across the often very variable conditions it encounters during infections. Differential allocation between those stages is equivalent to the fundamental life-history trade-off between survival and reproduction because gametocytes are responsible for between-host transmission (i.e. reproduction of the infection) whereas asexual parasites mediate host exploitation and within-host survival. A suite of within-host models reveal that malaria parasites could gain considerable fitness benefits in the face of low levels of drug treatment if they reduce their investment into gametocyte production ("reproductive restraint"), thereby assuring the continuity of the infection and capitalising on opportunities for future transmission. In contrast, high levels of drug treatment typically select parasites to commit all of their resources to gametocyte production ("terminal investment"), to escape a host that does not offer much opportunity for future transmission. My experiments reveal that P. chabaudi increases both its reproductive investment and its asexual replication rate in anaemic hosts (i.e. host that have a low density of red blood cells), suggesting that parasites profit from host anaemia and can afford high investment in gametocytes ("affluent investment"). I also uncover plasticity in a number of traits that underpin asexual replication rate, including invasion preference for different ages of red blood cells, but it is plasticity in the number of progeny (merozoites) per infected cell that is the main contributor to asexual replication rate. My experiments also reveal genetic variance in plasticity of the life-history traits investigated, which has profound implications for their evolution. Furthermore, plastic modification of these traits is associated with minimal costs or constraints, so that parasites can rapidly match life-history traits appropriately to the within-host environment. Severe anaemia is one of the deadliest symptoms of malaria, so observing that virulence and infectiousness increases in anaemic hosts has also fundamental clinical implications. Finally, the empirical and theoretical observations of affluent investment, reproductive restraint and terminal investment match theoretical predictions of how organisms should behave in varying environments, confirming P. chabaudi as a useful model system to test life-history theory.
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Tobias, Lynette. "The pregnant mouse model of brucellosis: the pathology and protection studies comparing Brucella abortus strains 2308, 19 and RB51." Diss., Virginia Tech, 1991. http://hdl.handle.net/10919/39917.
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Ward, Brittney M. "Analyzing consequences to astrocytes in a mouse model of brain arteriovenous malformation." Ohio University Honors Tutorial College / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ouhonors1619298440206905.
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Chokalingam, Kumar. "Transgenic Mouse Model: Examination of Healing, Development and Mechanical Response of Cells." University of Cincinnati / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1259076989.
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Farr, Tracy Deanne, and University of Lethbridge Faculty of Arts and Science. "A mouse model for studying stroke induced impairments, recovery, and compensation in the motor cortex." Thesis, Lethbridge, Alta. : University of Lethbridge, Faculty of Arts and Science, 2003, 2003. http://hdl.handle.net/10133/156.
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Stroke is the third leading cause of death and survivors suffer motor impairments. The rodent sensorimotor system is similar to the human's, making rodents a good model to study the effects of stroke. Transgenic technology makes the mouse a desirable stroke model, however, there are few behavioural tests to assess behavioural outcome. This thesis evaluates mice subjected to permanent or temporary occlusion focal motor cortex strokes in a skilled reaching task. The first experiment documents changes in skilled movements in mice with a permanent occlusion focal motor cortex stroke. The second experiment is identical but uses a temporary occlusion focal motor cortex stroke. The third experiment compares the two strokes. The results indicate permanent occlusion mice suffer great impairments, and a larger injury, than temporarily occluded animals. The mice with the largest insults were most impaired. Mice make an excellent behavioural and genetic model for studying motor system stroke.<br>viii, 115 leaves : ill. ; 29 cm.
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Paliobeis, Andrew S. "Effects of Pramlintide on Mitochondrial Dynamics and Health in the Alzheimer's Disease APP/PS1 Mouse Model." Kent State University Honors College / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ksuhonors1494262713896063.
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Kennedy, Samantha F. "Possible breakdown of dopamine receptor synergism in a mouse model of Huntington's Disease." ScholarWorks@UNO, 2017. https://scholarworks.uno.edu/td/2415.
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The model of basal ganglia function proposed by Albin, Young and Penney (1989) describes two anatomically independent motor pathways, the direct and indirect. However, under normal conditions striatal dopamine (DA) is required for the expression of motor behavior, and DAergic control of the two pathways (via D1 and D2 receptors, respectively) is dependent on co-activation. We tested for a possible breakdown of D1/D2 synergism using transgenic R6/1 mice bearing the human huntingtin allele (Htt). Motor stereotypy, observed prior to the onset of HD-related symptoms, was rated on a 5-point scale following activation of: A) D1 receptors alone, B) D2 receptors alone, and C) stimulation of both D1 and D2 receptors. Results revealed that mice with the HD allele, like their WT litter mates, depend on the co-activation of the indirect and direct motor pathways to facilitate deliberate behavior.
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Creamer, Michelle. "UVB Exposure and Topical Estrogen Effects on the Development of Skin Cancer in a Pre- and Post-Menopausal Mouse Model." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1337631752.
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Perlaza, Blanca-liliana. "Analysis of immune responses related to protection against P. Falciparum pre-erythrocytic stages : aotus lemurinus griseimembra as a model for malaria vaccine research." Rouen, 2000. http://www.theses.fr/2000ROUEM008.
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Le paludisme est une des maladies infectieuses les plus meurtrières pour l'homme. Le développement d'un vaccin contre Plasmodium falciparum, l'agent responsable du paludisme léthal, repose sur l'identification des antigènes cibles de mécanismes immuns protecteurs et sur l'utilisation de modèles animaux appropriés pour l'induction et l'étude de tels mécanismes in vivo. Notre laboratoire a identifié et caractérisé une série d'antigènes pré-érythrocytaires de P. Falciparum (LSA1, LSA3, SALSA et STARP). Parmi eux, LSA3 est le plus prometteur du point de vue vaccinal, et ce, dans différents modèles animaux. La présente thèse décrit les réponses immunitaires induites chez l'animal par ces antigènes, et confirme le potentiel vaccinal de la molécule LSA3 dans deux modèles d'étude pré-cliniques: la souris et le singe Aotus. L'Aotus lemurinus griseimembra est un petit singe du nouveau monde. Nous avons pu, i) confirmer que cette espèce est sensible à l'infection par des sporozoïtes de P. Falciparum; ii), définir les conditions de maintien du parasite par passages cycliques entre Aotus et moustiques; iii) montrer l'induction de réponses immunes humorales et cellulaires chez des singes immunisés soit avec un mélange de 4 lipopeptides dérivés des 4 antigènes, soit avec des protéines recombinantes de LSA3, enfin, iv), pour la première fois, nous avons pu induire une protection contre une infection d'épreuve par des sporozoites de P. Falciparum chez des singes Aotus immunisés par LSA3. Grâce aux progrès dans la synthèse des peptides, nous avons utilisé 17 peptides synthétiques longs (PSL) couvrant l'ensemble de la protéine LSA3 pour confirmer la bonne antigénicité de la molécule chez des individus naturellement infectés par P. Falciparum. En outre, ces PSL se sont révélés fortement immunogènes chez la souris, induisant des réponses T auxiliaires, CTL et anticorps spécifiques. De même, de fortes réponses de type Th1 ont été induites contre différentes régions de la molécule chez des souris immunisées par de l'ADN plasmidique codant LSA3. Ce même protocole d'immunisation nous a permis de protéger des souris contre une infection d'épreuve par des sporozoites de P. Yoelii. L'ensemble de ces données renforcent l'intérêt vaccinal de la molécule LSA3 et valident en même temps le singe Aotus comme modèle d'étude préclinique pour le développement de vaccins pré-érythrocytaires contre la malaria. Ils offrent la perspective d'études sur les étapes encore mal connues du développement pré-érythrocytaire de P. Falciparum<br>Malaria is one of the most evasive infectious diseases in the world. The development of a vaccine against the human malaria parasite Plasrnodium falciparum requires first, the identification of the parasitic antigens involved in protection, and second, the use of appropriate animal models to study protective immune mechanisms and to optimize immunization protocols intended to induce them. A subset of P. Falciparum preerythrocytic antigens (LSA l, LSA3, SALSA and STARP) have been identified and characterized. Among them, LSA3 displayed promising antigenic, immunogenic and protective efficacy in différent animal models. The current thesis describes the immune responses induced by these antigens, particularly the immunogenicity and protective potential of LSA3 in mice and Aotus monkeys. Aotus lemurinus griseirnembra is a small New World monkey. We confirmed that the species A. /. Griseimembra is susceptible to infection by P. Falciparum sporozoites and we were able to maintain the parasite by cyclical passages through Aotns and mosquitoes. When Aotus lemurinus were immunized with either, a mixture of lipopeptides from 4 P. Falciparum preerythrocytic antigens or LSA3 recombinant proteins, the monkeys were able to induce high cellular and humoral immune responses, indicating that it is a suitable animal model for evaluating immunogenicity of pre-erythrocytic antigens. Finally, for the first time we report evidence of protection against challenge with P. Falciparum sporozoites in Aotus monkeys. Taking advantage of the recent advances in peptide synthesis, we used 17 Long Synthetic Peptides (LSP) covering all the LSA3 protein to confirm the antigenicity of LSA3 antigen in individuals highly exposed to natural P. Falciparum infections. In addition, these LSP were found to be strongly immunogenic in mice, eliciting T-helper, CTL responses and specific antibody production. On the other hands, LSA3-DNA-based immunization in mice induced high immune responses against different regions of the molecule and preferentially generated responses Th 1-type. Moreover, this immunization protocol was able to induce protection against the challenge with P. Yoelii sporozoites. These findings confirm previous results about the vaccine potential of LSA3 and allow to validate Aolus monkeys as model for preerythrocytic malaria vaccines research. They open the way to a great number of future studies on P. Falciparum pre-erythrocytic stages
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King, Marie A. "The Humanized Mouse Model: The Study of the Human Alloimmune Response: A Dissertation." eScholarship@UMMS, 2008. https://escholarship.umassmed.edu/gsbs_diss/374.
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The transplantation of allogeneic cells and tissues for the treatment of human disease has been a life-saving procedure for many thousands of patients worldwide. However, to date, neither solid organ transplantation nor bone marrow transplantation have reached their full clinical potential. Significant limitations to the advancement of clinical transplantation stem from our current inability to prevent the rejection of allogeneic tissues by the immune system of the host. Similarly, in patients that receive allogeneic bone marrow transplants, we cannot permanently prevent the engrafted immune system from mounting a response against the patient. This problem, termed graft versus host disease is the most prevalent cause of morbidity and mortality in recipients of allogeneic bone marrow transplants.
Clinically, we rely on lifelong immunosuppression to prolong survival of allogeneic tissues within the host. Our currently available therapeutics burden patients with side-effects that range from being unpleasant to life-threatening, while in most cases offering only a temporary solution to the problem of alloimmunity. Efforts are underway to develop protocols and therapeutics that more effectively prevent the pathology associated with alloimmunity. To minimize patient risk, extensive pre-clinical studies in laboratory animals are conducted to predict clinical responses. In the case of immunologic studies, many of these pre-clinical studies are carried out in murine models. Unfortunately, studies of murine immunity often do not predict outcomes in the clinic. One approach to overcome this limitation is the development of a small animal model of the human immune system.
In this dissertation, we hypothesized that NOD-scid IL2rγnull mice engrafted with human peripheral blood mononuclear cells (PBMC), termed the hu-PBMC-NOD-scid IL2rγnull model, would provide a model that more accurately reflects human immunity in vivo than other models currently available. To investigate this possibility, we first investigated whether NOD-scid IL2rγnull mice were able to support the engraftment of human PBMC. We found that NOD-scid IL2rγnull mice engraft with human PBMC at much higher levels then the previous gold standard model, the NOD-scid mouse. We then investigated the kinetics of human cell engraftment, determined the optimal cell dose, and defined the influence of injection route on engraftment levels. Even at low PBMC input, NOD-scid IL2rγnullmice reproducibly support high levels of human PBMC engraftment. In contrast to previous stocks of immunodeficient mice, we observed low intra- and interdonor variability of engraftment.
We next hypothesized that the human PBMC engrafted in NOD-scid IL2rγnull mice were functional and would reject transplanted allogeneic human tissues. To test this, human islets were transplanted into the spleen of chemically diabetic NOD-scid IL2rγnull mice with or without intravenous injection of HLA-mismatched human PBMC. In the absence of allogeneic PBMC, the human islets were able to restore and maintain normoglycemia. In contrast, human islet grafts were completely rejected following injection of HLA-mismatched human PBMC as evidenced by return to hyperglycemia and loss of human C-peptide in the circulation. Thus, PBMC engrafted NOD-scid IL2rγnull mice are able to provide an in vivomodel of a functional human immune system and of human islet allograft rejection.
The enhanced ability of NOD-scid IL2rγnull mice to support human cell engraftment gave rise to the possibility of creating a model of graft versus host disease mediated by a human immune system. To investigate this possibility, human PBMC were injected via the tail vein into lightly irradiated NOD-scid IL2rγnull mice. We found that in contrast to previous models of GVHD using human PBMC-injected immunodeficient mice, these mice consistently (100%) developed GVHD following injection of as few as 5x106PBMC, regardless of the PBMC donor used. We then tested the contribution of host MHC in the development of GVHD in this model. As in the human disease, the development of GVHD was highly dependent on host expression of MHC class I and class II molecules.
To begin to evaluate the extent to which the PBMC-engrafted NOD-scid IL2rγnull humanized mouse model of GVHD represents the clinical disease, we tested the ability of a therapeutic in clinical trials to modulate GVHD in these mice. In agreement with the clinical experience, we found that interrupting the TNFα signaling cascade with etanercept delayed the onset and severity of disease in this model. In summary, we conclude that humanized NOD-scid IL2rγnull mice represent an important surrogate for investigating in vivo mechanisms of both human islet allograft rejection and graft versus host disease.
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Mercurio, Andrew David. "Effects of Extensive Periosteal Stripping on the Microstructure and Mechanical Properties of Cortical Bone." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1306435727.
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Tian, Nan. "SLEEP-RELATED GENERALIZED TONIC SEIZURE AND HIGH FREQUENCY OSCILLATION (HFOs) IN A MESIAL TEMPORAL LOBE EPILEPSY MOUSE MODEL." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1277440218.
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Durst, Mattea Sophie [Verfasser]. "Evaluating the Pain Management in a Mouse Osteotomy Model - Integrating a Refinement Approach in a Basic Research Study / Mattea Sophie Durst." Berlin : Freie Universität Berlin, 2019. http://d-nb.info/1192755685/34.
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Zorko, Nicholas Alexander. "The Role of the Mixed Lineage Leukemia Partial Tandem Duplicationin Acute Myeloid Leukemogenesis." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1374101112.
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Kok, Cornelius Wilhelmus. "Molecular characterization of human vaginal mucosa obtained from fresh harvest and implants in an experimental nude mouse model." Thesis, Stellenbosch : University of Stellenbosch, 2011. http://hdl.handle.net/10019.1/6879.
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Thesis (MMedSc )--University of Stellenbosch, 2011.<br>ENGLISH ABSTRACT: The present study investigated in particularly the specific nature of the supporting stromal layer
located between the implanted human cyst and host murine tissue, which has yet to be reported.
During an initial phase of this study, the particular light microscopic properties of the existing
hematoxylin and eosin (H&E) stained experimental cyst was investigated, with regards to the
presence or absence of specific morphological features, namely spongiosis, exocytosis, epithelial
keratinization, epithelial thickness and hyperplasia, and the vascularity and fibrosis present in the
stroma of these experimental sections. Subsequent analysis reported significant spongiosis, in
addition to increased exocytosis of immune cells and epithelial keratinization in a number of
cysts. Additionally, increased epithelial thickness and hyperplasia was reported in only 2 / 10
experimental tissues, whereas increased vascularity was observed in the stroma following
analysis of H&E and Special staining, such as Verhoeff-von Gieson and Masson trichrome
results.
During the second phase of the study, immunohistochemical analysis with a particularly wide
array of antibodies raised against specific human and mouse antigens had been applied. This
involved automated immunohistochemical staining with mouse anti-human primary antibodies,
in addition to manual staining with rabbit anti-mouse primary antibodies. Subsequent
visualization was achieved by means of linking to biotinylated secondary antibodies, and
Streptavidin-HRP incubation for standard visualization, followed by counterstaining with
Hematoxylin.
Maintained positive expression of cytokeratins 5, 13, and 14 was demonstrated in both control
human vaginal mucosa and experimental cysts, whereas similar findings were not reported for
cytokeratin 1, given the vast keratinization which was observed. Human collagen type IV and
laminin of the basement membrane reported positive expression in 9 / 10 and 6 / 10 control
human vaginal mucosa tissues respectively. In comparison, negative mouse collagen type IV and
laminin was reported in most experimental cysts compared to positive staining in positive control
mouse tissues.
Immunohistochemical staining for human elastin, fibronectin, von Willebrand factor, and
fibroblasts revealed maintained positive staining in all control human vaginal mucosa and
experimental cysts. However, maintained expression of CD34 (endothelial marker), CD1a
(langerhans cells), and human VEGFR-3 in experimental cysts was not demonstrated, compared
to positive expression in control human vaginal mucosa.
Subsequent analysis of murine antigens illustrated uniformly negative staining for mouse
fibronectin, langerhans cells (CD207), and fibroblasts, in addition to negative staining in positive
control mouse tissue sections. Furthermore, negative staining for mouse VEGFR-2 was reported
in all experimental cysts; however strong positive staining of this marker in mouse kidney tissue
had been reported.
The findings of this study suggested that the exact nature of the stromal layer is of both human
and murine origin. Furthermore, the tissue region located beneath the human vaginal epithelium
is suggested to be of human nature, whereas the second distinct region located at the periphery of
experimental cyst tissues, is suggested to be murine origin; however the findings of
immunohistochemical analysis could not illustrate definitively the exact nature of the
intermediate stromal layer, but could in fact demonstrate a mixture of human and murine tissue.<br>AFRIKAANSE OPSOMMING: Die huidige studie het die spesifieke molekulêre en histologiese eienskappe van die stromale laag
geleë tussen menslike sist- en muis velweefsel bestudeer, wat tans nog nie bekend is nie.
Gedurende die eerste fase van hierdie studie is die besondere lig-mikroskopiese eienskappe van
die bestaande hematoksilien en eosien (H&E) eksperimentele siste bestudeer, met betrekking tot
die aan- of afwesigheid van spesifieke morfologiese eienskappe, naamlik spongiose, eksositose
van immuunselle, epiteel keratinisasie, epiteel dikte en hiperplasie, en laastens die stromale
vaskulariteit en fibrose. Gevolglike analise het daarop gedui dat beduidende spongiose,
eksositose en epiteel keratinisasie gevind word in die eksperimentele siste in vergelyking met
kontrole vaginal weefsel. Hierteenoor is die verdikking van die epiteel en hiperplasie in slegs 2 /
10 eksperimentele siste gevind, terwyl vermeerderde vaskulariteit aangedui is na gevolglike
H&E en spesiale (soos byvoorbeeld Verhoeff-von Gieson en Masson trichrome)
kleuringsresultate.
Die tweede fase van die studie het die immunokleuring met verskeie mens- en muis spesifieke
antiliggame behels, waarby die uitdrukking van verskeie mens antigene vergelyk is met dié van
muis. As sulks is ge-automatiseerde immunohistochemie toegepas met muis primêre
antiliggame, tesame met fisiese kleuring met konyn primêre antiliggame toegepas. Gevolglike
visualisasie is aangedui deur middel van binding met sekondêre antiliggaam en Streptavidin-
HRP, gevolg deur teenkleuring met Hematoksilien.
Algehele behoud van positiewe uitdrukking van sitokeratien 5, 13, en 14 is bevind, terwyl
sitokeratien 1 uitdrukking nie daarwerklik vergelykbaar is met dié van kontrole mens vaginale
weefsel nie. Die uitdrukking van mens kollageen IV en laminien van die basaal membraan is
verder bestudeer, en het egter positiewe kleuring in 9 / 10 en 6 / 10 van kontrole mens vaginale
mukosa aangedui. In vergelykking hiermee kon die huidige bevindings egter net positiewe
kleuring in 4 / 10 en 3 / 10 eksperimentele siste vir kollageen IV en laminien onderskeidelik,
illustreer.
Immunohistochemiese analise van menslike elastien, fibronektien, von Willebrand (vW) faktor
en fibroblaste het op deurgaans positiewe uitdrukking van hierdie merkers aangedui in beide
eksperimentele en kontrole menslike weefsel. In teenstelling hiermee is volgehoue uitdrukking
van CD34 (endoteel merker), CD1a (Langerhans sel merker) en mens VEGFR-3 in
ekperimentele siste egter nie illustreerbaar nie, in vergelykking met deurgaans positiewe
uitdrukking van hierdie antigene in kontrole mens vaginale mukosa.
In opvolging is deurgaans negatiewe uitdrukking van muis fibronektien, langerhans sel (CD207)
en fibroblaste bevestig, terwyl negatiewe kleuring ook deurgaans in positiwe kontrole muis
weefsel, bekom deur die disseksie van ‘n naakte muis, gevind is. Verder is ook negatiewe
kleuring vir VEGFR-2 in alle eksperimentele siste gevind, terwyl egter sterk positiewe kleuring
in muis nierweefsel as positiewe weefsel gevind is.
Die resultate van die huidige studie het daarop gedui dat die stromale laag onderliggend tot mens
vaginale epiteel van menslike oorsprong is, terwyl die periferale stroma onderliggend tot muis
velweefsel, ongetwyfeld van muis oorsprong is. Laastens kon die spesifieke oorsprong van die
tussenliggende stroma nie aangedui word nie, maar dat dit moontlik uit beide menslike- en
muisweefsel bestaan.
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Burke, Steven Russell Alan. "Assessment of In Vivo Muscle Force in the R6/2 Mouse Model of Huntington's Disease Using Newly Designed Force Rig." Wright State University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=wright1610360658382723.
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Gao, Juehua. "Biological functions and molecular mechanisms of the interleukin-4 signaling pathways in autoimmune exocrinopathy using the nod.b10.h2b mouse model of sjogren's syndrome." [Gainesville, Fla.] : University of Florida, 2004. http://purl.fcla.edu/fcla/etd/UFE0006639.
Full textAbstract:
Thesis (Ph. D.)--University of Florida, 2004.<br>Typescript. Title from title page of source document. Document formatted into pages; contains 152 pages. Includes Vita. Includes bibliographical references.
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Henninger, Nils. "Inhibiting Axon Degeneration in a Mouse Model of Acute Brain Injury Through Deletion of Sarm1." eScholarship@UMMS, 2017. http://escholarship.umassmed.edu/gsbs_diss/900.
Full textAbstract:
Traumatic brain injury (TBI) is a leading cause of disability worldwide. Annually, 150 to 200/1,000,000 people become disabled as a result of brain trauma. Axonal degeneration is a critical, early event following TBI of all severities but whether axon degeneration is a driver of TBI remains unclear. Molecular pathways underlying the pathology of TBI have not been defined and there is no efficacious treatment for TBI.
Despite this significant societal impact, surprisingly little is known about the molecular mechanisms that actively drive axon degeneration in any context and particularly following TBI. Although severe brain injury may cause immediate disruption of axons (primary axotomy), it is now recognized that the most frequent form of traumatic axonal injury (TAI) is mediated by a cascade of events that ultimately result in secondary axonal disconnection (secondary axotomy) within hours to days.
Proposed mechanisms include immediate post-traumatic cytoskeletal destabilization as a direct result of mechanical breakage of microtubules, as well as catastrophic local calcium dysregulation resulting in microtubule depolymerization, impaired axonal transport, unmitigated accumulation of cargoes, local axonal swelling, and finally disconnection. The portion of the axon that is distal to the axotomy site remains initially morphologically intact. However, it undergoes sudden rapid fragmentation along its full distal length ~72 h after the original axotomy, a process termed Wallerian degeneration.
Remarkably, mice mutant for the Wallerian degeneration slow (Wlds) protein exhibit ~tenfold (for 2–3 weeks) suppressed Wallerian degeneration. Yet, pharmacological replication of the Wlds mechanism has proven difficult. Further, no one has studied whether Wlds protects from TAI. Lastly, owing to Wlds presumed gain-of-function and its absence in wild-type animals, direct evidence in support of a putative endogenous axon death signaling pathway is lacking, which is critical to identify original treatment targets and the development of viable therapeutic approaches.
Novel insight into the pathophysiology of Wallerian degeneration was gained by the discovery that mutant Drosophila flies lacking dSarm (sterile a/Armadillo/Toll-Interleukin receptor homology domain protein) cell-autonomously recapitulated the Wlds phenotype. The pro-degenerative function of the dSarm gene (and its mouse homolog Sarm1) is widespread in mammals as shown by in vitro protection of superior cervical ganglion, dorsal root ganglion, and cortical neuron axons, as well as remarkable in-vivo long-term survival (>2 weeks) of transected sciatic mouse Sarm1 null axons. Although the molecular mechanism of function remains to be clarified, its discovery provides direct evidence that Sarm1 is the first endogenous gene required for Wallerian degeneration, driving a highly conserved genetic axon death program.
The central goals of this thesis were to determine (1) whether post-traumatic axonal integrity is preserved in mice lacking Sarm1, and (2) whether loss of Sarm1 is associated with improved functional outcome after TBI. I show that mice lacking the mouse Toll receptor adaptor Sarm1 gene demonstrate multiple improved TBI-associated phenotypes after injury in a closed-head mild TBI model. Sarm1-/- mice developed fewer beta amyloid precursor protein (βAPP) aggregates in axons of the corpus callosum after TBI as compared to Sarm1+/+ mice. Furthermore, mice lacking Sarm1 had reduced plasma concentrations of the phosphorylated axonal neurofilament subunit H, indicating that axonal integrity is maintained after TBI. Strikingly, whereas wild type mice exhibited a number of behavioral deficits after TBI, I observed a strong, early preservation of neurological function in Sarm1-/- animals. Finally, using in vivo proton magnetic resonance spectroscopy, I found tissue signatures consistent with substantially preserved neuronal energy metabolism in Sarm1-/- mice compared to controls immediately following TBI. My results indicate that the Sarm1-mediated prodegenerative pathway promotes pathogenesis in TBI and suggest that anti-Sarm1 therapeutics are a viable approach for preserving neurological function after TBI.
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Cromwell, Mary A. "The Role of T Lymphocytes in the hu-PBMC-SCID Mouse Model of Epstein-Barr Virus-Associated Lymphoproliferative Disease." eScholarship@UMMS, 1995. https://escholarship.umassmed.edu/gsbs_diss/158.
Full textAbstract:
Epstein-Barr virus (EBV) is associated with a spectrum of benign and malignant lymphoproliferative disorders, including acute infectious mononucleosis (IM), Burkitt's lymphoma (BL) and immunosuppression-associated B cell lymphoproliferative disease (LPD). Immunosurveillance mediated by virus-specific cytotoxic T lymphocytes is believed to protect immunocompetent hosts from EBV-associated lymphoma and LPD. Due to the lack of an adequate animal model, however, the precise immunologic mechanisms which provide this protection have not been directly demonstrated in vivo.
Human peripheral blood mononuclear cell-reconstituted C.B.-17-scid/scid mice (hu-PBMC-SCID mice) develop EBV-positive LPD following intraperitoneal injection of PBMC from EBV-seropositive donors. The SCID mouse disease mirrors human EBV-associated LPD in morphology, presence of the EBV genome, clonality, and patterns of expression of latent viral cellular differentiation antigens. The hu-PBMC-SCID mouse provides a unique small animal model of EBV+ LPD, and it was used in this study to examine the role of CD8+ CTL in controlling LPD. Survival time increase significantly when EBV-specific cytotoxic T-cell lines (CTL) are adoptive transferred into hu-PBMC-SCID mice, demonstrating suppression of LPD in vivoby a CTL-mediated virus-specific mechanism. Survival time also increases significantly with administration of alloreactive CTL lines, suggesting that a non-virus-specific mechanism also contributes to control of EBV-associated LPD by CTL.
NOD-SCID mice reconstituted with PBMC from donors with latent EBV infection develop EBV+ LPD with significantly less frequency than do C.B.17-SCID mice reconstituted with PBMC from the same donors. Administration of anti-CD8 mAb to these mice depletes human CD8+ cells and increases the incidence of LPD to 100%, demonstrating that CD8+ T cells are neccessary for protection from EBV-associated LPD. Adoptive transfer of human CD8+ T cells, but not CD4+ T cells, prevents LPD in CD8-depleted NOD-SCID mice. In vivo depletion of CD4+ T cells prevents engraftment of human T cells, and LPD does not develop in most mice after CD4+ cell depletion. These studies are the first to directly demonstrate both the protective role of CD8+ T cells and a requirement for CD4+ T cells in EBV -associated LPD in an in vivo model.
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Painter, Palak Rajeshkumar. "Quantitative analysis of glycinergic neurons including Ia inhibitory interneurons in the ventral spinal cord using a BAC-GlyT2-eGFP transgenic mouse model." Wright State University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=wright1347911464.
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Golden, Jackelyn B. "Abnormalities in the Adhesion and Aggregation Profiles of Circulating Monocytes in Psoriasis." Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1441361209.
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Akiel, Maaged A. "CHARACTERIZATION OF THE ROLE OF INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 7 (IGFBP7) USING A GENETIC KNOCKOUT MOUSE MODEL." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4695.
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In the US, the incidence and mortality rates of hepatocellular carcinoma (HCC) are alarmingly increasing since no effective therapy is available for the advanced disease. Activation of IGF signaling is a major oncogenic event in diverse cancers, including HCC. Insulin-like growth factor binding protein-7 (IGFBP7) inhibits IGF signaling by binding to IGF-1 receptor (IGF-1R) and functions as a potential tumor suppressor for hepatocellular carcinoma (HCC). IGFBP7 abrogates tumors by inducing cancer-specific senescence and apoptosis and inhibiting angiogenesis. We now document that Igfbp7 knockout (Igfbp7-/- ) mouse shows constitutive activation of IGF signaling, presents with pro-inflammatory and immunosuppressive microenvironment, and develops spontaneous tumors in lungs and liver and markedly accelerated carcinogen-induced HCC. Loss of Igfbp7 resulted in increased proliferation and decreased senescence in hepatocytes and mouse embryonic fibroblasts that could be blocked by an IGF-1 receptor inhibitor. A significant inhibition of genes regulating immune surveillance was observed in Igfbp7-/- livers which was associated with marked inhibition in antigen cross presentation by Igfbp7-/- dendritic cells. IGFBP7 overexpression inhibited growth of HCC cells in syngeneic immune competent mice, which could be abolished by depletion of CD4+ or CD8+ T lymphocytes. Our studies unravel modulation of immune response as a novel component of pleiotropic mechanisms by which IGFBP7 suppresses HCC. Even though HCC has an immunosuppressive milieu, immune targeted therapies are beginning to demonstrate significant objective responses in clinical trials. IGFBP7 might be an effective anti-HCC therapeutic by directly inhibiting cancer cells and stimulating an anti-tumor immune response.
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Huettner, Lauren E. "Development and Characterization of Ectromelia Virus-Moscow in the BALB/c Mouse Model for Smallpox Therapeutic and Prophylaxis Drug Efficacy Testing Under the FDA Animal Rule." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1397642415.
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Balaji, Swathi. "In situ tissue engineering using angiogenic peptide nanofibers to enhance diabetic wound healing." University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1291151135.
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Dai, Lu. "EFFECTS OF CHROMIUM ON MOUSE SPLENIC T LYMPHOCYTES AND EFFECTS OF ETHANOL EXPOSURE DURING EARLY NEURODEVELOPMENT ON BEHAVIORS IN MICE." UKnowledge, 2017. https://uknowledge.uky.edu/toxicology_etds/18.
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The dissertation consists of three major projects with the focus on the immunotoxicity of chromium and the behavior disorders caused by early ETOH exposure respectively.
Hexavalent chromium [Cr(VI)] is widely used in various industrial processes and has been recognized as a carcinogen. As the first line of host defense system, the immune system can be a primary target of Cr(VI). T cell population represents a major arm of the immune system that plays a critical role in host anti-tumor immunity. Dysfunction of T cells compromises host anti-tumor immunity resulting in oncogenesis. Using mouse splenic T cells as an in vitro model system, the present study assessed the effects of Cr(VI) on T cell functions, as the first step of our investigation of the mechanism underlying Cr(VI)-inhibited immunosurveillance and carcinogenesis. Our results showed that Cr(VI) decreased the viability of CD4+ and CD8+ T cells, inhibited T cell activation, functions, including cytokine release, and degranulation.
Fetal ethanol (ETOH) exposure can damage the developing central nervous system and lead to cognitive and behavioral deficits, known as fetal alcohol spectrum disorders (FASD). The use of animal models, especially mouse models is essential for investigating the neurogenetic mechanism of fetal ETOH effects and screening pharmacotherapies against it, due to the extensive knowledge of mouse genetics. However, the availability of mouse model is limited. Via adopting various dosage, timing and administration routes of ETOH exposure, we developed two mouse models to assess behavioral or cognitive changes caused by fetal ETOH exposure in pre-weaning and adolescent period. Our results show that high dosage of ETOH exposure (4 g/kg) during PD 4-10 resulted in hyperactivity, disinhibition, and deficits in learning and memory in mouse offspring, which lays the groundwork for the future FASD research.
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Wyse, Ana Paula Pintado. "Controle ótimo do vetor da malária para o modelo matemático sazonal." Laboratório Nacional de Computação Científica, 2007. https://tede.lncc.br/handle/tede/69.
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Previous issue date: 2007-04-09<br>Conselho Nacional de Desenvolvimento Cientifico e Tecnologico<br>In the Amazonian region occurs a variation in the malaria incidence, which is related to the pluviometric variation annual. The mathematical model proposed here considers this seasonality and different treatment intensities accessible to the infected people. The numerical evidence the seasonal fluctuation and the relationship between the environment temperature and treatment efficiency, showing that the temperature increase strongly affects the extrinsic latent period,reducing the healthy care efficiency. Because malaria treatment already exists it should be import. For another hand, even the investment in treatment is an efficient form to block the epidemy, it is not always sufficient, because the protozoan has been more resistent to the medicine; then scientists are creating transgenic mosquitoes refractory to malaria to couple with wild one, generating descending transgenic. To avaliate this situation, we consider here a mathematical model that describes the relatioship between these populations. Then, we formulate and solve an optimal control problem indicating how the transgenic mosquitoes should be introduced in the environment. The numerical simulations show the effectiveness of the control.<br>Na Amazônia ocorre uma variação na incidência de malária que está intimamente relacionada à variação pluviométrica ao longo do ano. O modelo matemático aqui proposto considera esta sazonalidade e diferentes intensidades de tratamento acessíveis às pessoas infectadas. Experimentos numéricos descrevem a flutuação sazonal e evidenciam uma relação inversa entre a temperatura e eficiência do tratamento, mostrando que um aumento na temperatura afeta fortemente o período latente extrínseco, reduzindo a eficiência do investimento em saúde. Como o tratamento para os infectados existe, é importante concentrar esforços nesse sentido para obter sucesso no controle da malária. Por outro lado, embora o investimento em tratamento seja uma forma eficaz de impedir a epidemia, isso nem sempre é suficiente, pois é fato que o protozoário tem se mostrado cada vez mais resistente aos medicamentos; por esse motivo, cientistas estão criando mosquitos transgênicos refratários à malária que devem acasalar com os mosquitos selvagens, gerando descendência transgência. Para avaliar esta situação, consideramos neste trabalho um modelo matemático que descreve de maneira simplificada a relação entre estas duas populações. A partir desse modelo, formulamos e resolvemos um problema de controle ótimo indicando uma forma adequada de introduzir esses mosquitos transgênicos. Experimentos numéricos mostram a eficácia do controle adotado.
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Smith, Porsha L. "Protein Arginine Methyltransferase 5 as a Driver of Lymphomagenesis." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1468975682.
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Toro, Gabriela. "Gene Therapy for Amyotrophic Lateral Sclerosis: An AAV Mediated RNAi Approach for Autosomal Dominant C9ORF72 Associated ALS." eScholarship@UMMS, 2019. https://escholarship.umassmed.edu/gsbs_diss/1020.
Full textAbstract:
Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease that affects motor neurons causing progressive muscle weakness and respiratory failure. In 2011, the presence of a hexanucleotide repeat expansion within chromosome 9 open reading frame 72(C9ORF72) was identified in ALS patient samples, becoming the major known genetic cause for ALS and frontotemporal dementia (FTD). Carriers of this mutation present reduced levels of C9ORF72 mRNA, RNA foci produced by the aggregating expansion and toxic dipeptides generated through repeat-associated non-ATG translation. These findings have led to multiple hypotheses on the pathogenesis of C9ORF72: 1) Haploinsufficiency, 2) RNA gain-of-function, 3) RAN Translation, and 4) Disrupted nucleocytoplasmic trafficking. Due to lack of treatments for this disease, we have pursued an AAV-RNAi dependent gene therapy approach, using an artificial microRNA (amiR) packaged in a recombinant adeno-associated virus (rAAV). After validating our in vitro results, we advanced to in vivo experiments using transgenic mice that recapitulate the major histopathological features seen in human ALS/FTD patients. Adult and neonate mice were injected through clinically relevant routes and our results indicate that AAV9-mediated amiR silencing not only reduced mRNA and protein levels of C9ORF72 but also the expansion derived toxic GP dipeptides. Although our amiR is not targeting the expansion itself but exon 3, we illustrate here that the evident dipeptide decrease is achievable due to the presence of aberrant transcripts in the cytoplasm containing miss-spliced Intron-HRE-C9ORF72 species. These encouraging results have led to the continued testing of this treatment as a therapeutic option for C9ORF72 - ALS patients.
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Nun, Nicholas. "Improving Skin Wound Healing Using Functional Electrospun Wound Dressings and 3D Printed Tissue Engineering Constructs." University of Akron / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=akron1617985844538101.
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Chambers-Turner, Ruth C. "The IM-9 cell line: a model for evaluating TCDD-induced modulation of the polymorphic human hs1,2 enhancer within the 3' immunoglobulin heavy chain regulatory region." Wright State University / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=wright1269027538.
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Smith, Jordan L. "Reversing Cancer Cell Fate: Driving Therapeutic Differentiation of Hepatoblastoma to Functional Hepatocyte-Like Cells." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1067.
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Background & Aims: Despite advances in surgical care and chemotherapeutic regimens, the five-year survival rate for Stage IV Hepatoblastoma (HB), the predominant pediatric liver tumor, remains at 27%. YAP1 and β-Catenin co-activation occurs in 80% of children’s HB; however, a lack of conditional genetic models precludes exploration of tumor maintenance and therapeutic targets. Thus, the clinical need for a targeted therapy remains unmet. Given the predominance of YAP1 and β-catenin activation in children’s tumors, I sought to evaluate YAP1 as a therapeutic target in HB.
Approach & Results: Herein, I engineered the first conditional murine model of HB using hydrodynamic injection to deliver transposon plasmids encoding inducible YAP1S127A, constitutive β-CateninDelN90, and a luciferase reporter to murine liver. Tumor regression was evaluated using in vivo bioluminescent imaging, and tumor landscape characterized using RNA sequencing, ATAC sequencing and DNA foot-printing. Here I show that YAP1 withdrawal in mice mediates >90% tumor regression with survival for 230+ days. Mechanistically, YAP1 withdrawal promotes apoptosis in a subset of tumor cells and in remaining cells induces a cell fate switch driving therapeutic differentiation of HB tumors into Ki-67 negative “hbHep cells.” hbHep cells have hepatocyte-like morphology and partially restored mature hepatocyte gene expression. YAP1 withdrawal drives formation of hbHeps by modulating liver differentiation transcription factor (TF) occupancy. Indeed, tumor-derived hbHeps, consistent with their reprogrammed transcriptional landscape, regain partial hepatocyte function and can rescue liver damage in mice.
Conclusions: YAP1 withdrawal, without modulation of oncogenic β-Catenin, significantly regresses hepatoblastoma, providing the first in vivo data to support YAP1 as a therapeutic target for HB. Modulating YAP1 expression alone is sufficient to drive long-term regression in hepatoblastoma because it promotes cell death in a subset of tumor cells and modulates transcription factor occupancy to reverse the fate of residual tumor cells to mimic functional hepatocytes.
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"Mouse orthotopic model for therapeutic bladder cancer research." 2014. http://library.cuhk.edu.hk/record=b6116078.
Full textAbstract:
Objectives: To establish a mouse orthotopic bladder cancer model with consistent tumor-take rate. This orthotopic model was subsequently used to evaluate small animal imaging techniques and investigate new therapeutic agents for bladder cancer treatment.<br>Materials and Methods: Different orthotopic implantation techniques have been tested. MBT-2 cells and syngeneic C3H/He mice were used in all experiments. Chemical bladder pre-treatment with different agents (saline, hydrochloric acid, trypsin and poly-L-lysine) and different concentration of instilled tumor cells (1 x 10⁶ or 2 x 10⁶) were investigated. In the second part of the experiment, trans-abdominal micro-ultrasound imaging (MUI) technique was investigated and validated. Bladder tumor growths were monitored with longitudinal measurement. Mice were killed at every MUI session. Bladder tumor volumes were measured and correlated with gross stereomicroscopy. Using the optimized orthotopic bladder cancer model, targeted contrast enhanced micro-ultrasound imaging has been investigated. VEGFR2 targeted contrast agent was prepared and injected intravenously before imaging sessions. The intra-tumoral perfusion, VEGFR2 expression and blood volume in real time were quantified. Contrast enhanced MUI was performed on Days 14 and 21. The feasibility of targeted contrast enhanced micro-ultrasound imaging was confirmed. After the establishment of orthotopic model and in vivo molecular imaging techniques, this robust platform was used for investigating new treatment agent in localized bladder cancer. Tumor-bearing mice were randomized into control and sunitinibtreated (40 mg/kg) groups. Tumor volume, intra-tumoral perfusion, and in vivo VEGFR2 expression were measured using a targeted contrast-enhanced micro-ultrasound imaging system. The effects of sunitinib malate on angiogenesis and cellular proliferation were measured by CD31 and Ki-67 immunohistochemistry. The clinical outcomes including total bladder weight, tumor stage, and survival were evaluated.<br>Results: A consistent tumor take-rate of over 90% was achieved by using poly-L-lysine pretreatment with 2 x 10⁶ MBT-2 cells in all of the experiments. MUI identified all tumors that were present on final histology. Measurements of tumor size by MUI and gross microscopy had a high correlation coefficient (r = 0.97). Measurements of intra-tumoral perfusion and in vivo VEGFR2 expression were also proved to be feasible. After the technical refinement and modification, complete measurements could be performed in all mice (n = 10) at 2 consecutive imaging sessions. No adverse effects occurred due to anesthesia or the ultrasound contrast agent. This is the first report of applying targeted contrast enhanced MUI in orthotopic bladder cancer model. Finally, sunitinib was found to have significant tumor growth inhibition in both in vitro and in vivo experiments. In the orthotopic model, tumors in sunitinib-treated mice had reduced tumor volume and stage, lower proliferation index and micro-vessel density. Sunitinib prolonged survival in tumor-bearing mice as compared to control group.<br>Conclusions: The development of reliable orthotopic animal models assists in the discovery of novel therapeutic agents. The establishment in the methods of implantation with improved tumor-take rate and the advances in imaging technology form the important foundation of basic research in bladder cancer. Trans-abdominal MUI is proven to be a valuable tool for translational studies involving orthotopic mouse bladder cancer models. Furthermore, the first report of the application of targeted contrast enhanced MUI in deep-seated tumor in bladder has been published. It enables investigators to monitor tumor angiogenesis and vascular changes after treatment. It will be useful for direct, noninvasive, in vivo evaluation of anti-angiogenesis therapeutic agents. The preclinical study has demonstrated the activities of a new class of targeted therapy against localized bladder cancer in an orthotopic mouse model. Sunitinib inhibits tumor growth and thus decreases the tumor burden and prolongs survival compared with placebo. These results provide a rationale for future clinical trials using VEGFR-targeted treatments of localized bladder cancer in the neo-adjuvant and adjuvant settings.<br>Chan, Shu Yin Eddie.<br>Thesis (M.D) Chinese University of Hong Kong, 2014.<br>Includes bibliographical references (leaves 189-212).
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Abeysekera, Irushi Shamalka. "Effect of Epigallocatechin-3-gallate on Skeletal and Cognitive Phenotypes in a Down Syndrome Mouse Model." Thesis, 2014. http://hdl.handle.net/1805/5628.
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Indiana University-Purdue University Indianapolis (IUPUI)<br>Down syndrome (DS), a genetic disorder that affects ~1 in 700 live births, is caused by trisomy of human chromosome 21 (Hsa21). Individuals with DS are affected by a wide spectrum of phenotypes which vary in severity and penetrance. However, cognitive and skeletal impairments can be commonly observed in all individuals with DS. To study these phenotypes, we utilized the Ts65Dn mouse model that carries three copies of approximately half the gene orthologs found on Hsa21 and exhibit similar phenotypes as observed in humans with DS. Individuals with DS and Ts65Dn mice have deficits in bone mineral density (BMD), bone architecture, bone strength, learning and memory. Over-expression of DYRK1A, a serine-threonine kinase encoded on Hsa21, has been linked to deficiencies in DS bone homeostasis and cognition. Epigallocatechin-3-gallate (EGCG), an aromatic polyphenol found in high concentrations in green tea, is a selective inhibitor of DYRK1A activity. Normalization of DYRK1A activity by EGCG therefore may have the potential to ameliorate skeletal and cognitive deficits. We hypothesized that supplements containing EGCG obtained from health food stores/ online vendors will not be as effective as EGCG from a chemical company in correcting bone deficits associated
with DS. Our results suggest that EGCG improves the bone mineral density of trisomic femurs significantly better than the supplements while the EGCgNOW supplement from NOW FOODS improves trabecular and cortical bone structure. The results from HPLC analysis of supplements showed the presence of other catechins in EGCgNOW and degradation analysis revealed the rapid degradation of supplements. Therefore we hypothesize that the presence of EGCG degradation products and other green tea catechins in supplements may play a role in the differential skeletal effects we observed. We further hypothesized that a three week treatment of adolescent mice with EGCG will lead to an improvement in the learning and memory deficits that are observed in trisomic animals in comparison to control mice. However, our results indicate that three weeks of low-dose EGCG treatment during adolescence is insufficient to improve hippocampal dependent learning and memory deficits of Ts65Dn mice. The possibility remains that a higher dose of EGCG that begins at three weeks but lasts throughout the behavioral test period may result in improvement in learning and memory deficit of Ts65Dn mice.
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Stringer, Megan Elizabeth. "Effect of Epigallocatechin-3-gallate on a pattern separation task and hippocampal neurogenesis in a mouse model of Down syndrome." Thesis, 2015. http://hdl.handle.net/1805/10037.
Full textAbstract:
Indiana University-Purdue University Indianapolis (IUPUI)<br>Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in an array of phenotypes including intellectual disability. Ts65Dn mice, the most extensively studied DS model, have three copies of ~50% of the genes on Hsa21 and display many phenotypes associated with DS, including cognitive deficits. DYRK1A is found in three copies in humans with Trisomy 21 and in Ts65Dn mice, and is involved in a number of critical pathways including CNS development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have shown that a three-week EGCG treatment (~10mg/kg/day) during adolescence normalizes skeletal abnormalities in Ts65Dn mice, yet the same dose did not rescue deficits in the Morris water maze spatial learning task (MWM) or novel object recognition (NOR). Others have reported that An EGCG dose of 2-3 mg per day (90mg/ml) improved hippocampal-dependent task deficits in Ts65Dn mice. The current study investigated deficits in a radial arm maze pattern separation task in Ts65Dn mice. Pattern separation requires differentiation between similar memories acquired during learning episodes; distinguishing between these similar memories is thought to depend on distinctive encoding in the hippocampus. Pattern separation has
been linked to functional activity of newly generated granule cells in the dentate gyrus. Recent studies in Ts65Dn mice have reported significant reductions in adult hippocampal neurogenesis, and after EGCG treatment, enhanced hippocampal neurogenesis. Thus, it was hypothesized that Ts65Dn mice would be impaired in the pattern separation task, and that EGCG would alleviate the pattern separation deficits seen in trisomic mice, in association with increased adult hippocampal neurogenesis. At weaning, Ts65Dn mice and euploid littermates were randomly assigned to the water control, or EGCG [0.4 mg/mL], with both treatments yielding average daily intakes of ~50 mg/kg/day. Beginning on postnatal day 75, all mice were trained on a radial arm maze-delayed non-matching-to-place pattern separation task. Euploid mice performed significantly better over training than Ts65Dn mice, including better performance at each of the three separations. EGCG did not significantly alleviate the pattern separation deficits in Ts65Dn mice. After the behavioral testing commenced, animals were given ad libitum food access for five days, received a 100mg/kg injection of BrdU, and were perfused two hours later. Coronal sections through the dorsal hippocampus were processed for BrdU labeling, and cells were manually counted throughout the subgranular zone of the dentate gyrus. The euploid controls had significantly more BrdU labeled cells than Ts65Dn mice, however, EGCG does not appear to increase proliferation of the hippocampal neuroprogenitor cells. This is the first report of deficits in Ts65Dn mice on a pattern separation task. To the extent that pattern separation depends on the functional involvement of newly generated neurons in an adult dentate gyrus, this approach in Ts65Dn mice may help identify more targeted pharmacotherapies for cognitive deficits in individuals with DS.
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Deitz, Samantha L. "Molecular Basis and Modification of a Neural Crest Deficit in a Down Syndrome Mouse Model." 2013. http://hdl.handle.net/1805/3354.
Full textAbstract:
Indiana University-Purdue University Indianapolis (IUPUI)<br>Down syndrome (DS) is the result of trisomy of human chromosome 21 (Hsa 21) and occurs in approximately 1/700 live births. Mouse models of DS have been crucial in understanding the gene-phenotype relationships that underlie many DS anomalies. The Ts65Dn mouse model, trisomic for half of the Hsa 21 orthologs replicates many DS phenotypes including craniofacial alterations such as a small, dysmorphic mandible, midface, and maxilla. Other mouse models, such as the Ts1Rhr which contains a triplication of 33 Hsa 21 orthologs, have been used to better understand the genes responsible for craniofacial alterations. Our laboratory has demonstrated that the postnatal mandibular phenotype found in Ts65Dn mice can be traced back to an original neural crest cell (NCc) deficit in the developing first pharyngeal arch (PA1) at embryonic day 9.5 (E9.5). Furthermore, evidence suggested that both a proliferation deficit in the PA1 and a migration deficit in the NCC from the neural tube (NT) could be the mechanism behind this deficit. However, the molecular mechanisms behind these deficits remain to be elucidated. Due to the involvement of the Hsa 21 genes DYRK1A and RCAN1 in regulation of signaling pathways including NFATc (NFAT2), a transcription factor known to influence cellular proliferation and, later, bone development, we hypothesized that dysregulation of these genes could underlie the cellular deficit in the PA1. Furthermore, we hypothesized that targeting Dyrk1a by decreasing activity or available protein could ameliorate the established deficits.
Through the use of RNA isolation techniques and cell culture systems of cell from the PA1 and NT of E9.5 Ts65Dn, Ts1Rhr, and control embryos, we established that trisomic genes Dyrk1a and Rcan1 ara dysregulated in both structures and that these two genes may interact. Furthermore, we established that a proliferation deficit in the Ts65Dn PA1 and a migration deficit in the Ts65Dn PA1 and NT exists at E9.5 and can be rescued to euploid levels in vitro with the addition of the Dyrk1a inhibitor, EGCG, a green tea polyphenol. We also confirmed that harmine, a more highly studied and specific Dyrk1a inhibitor, is capable of similar effects on proliferation of PA1 cell from E9.5 Ts65Dn embryos. Furthermore, when Ts65Dn pregnant mothers were treated with EGCG in vivo, the cellular deficit found in the developing E9.5 embryonic PA1 was rescued to near euploid volume and NCC number. Treatment with EGCG did not adversely impact litter size or embryonic development. Interestingly, euploid embryonic volume increased with EGCG treatment. Expression analysis of the E9.5 PA1 of EGCG treated Ts65Dn and control embryos revealed dysregulation of several genes involved in craniofacial and developmental pathways including Dyrk1a, Rcan1, Ets2 and members of the sonic hedgehog pathways. Our novel results provide a foundation for better understanding the molecular mechanisms of craniofacial development and may provide evidence-based therapeutic options to improve the quality of life for individuals with DS.
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Jurado, Jiménez Ángeles [Verfasser]. "Role of the co-inhibitory molecule PD-1 (CD279) and its ligand PD-L1 (CD274) in a mouse (Mus musculus; Linnaeus, 1758) model of malaria / submitted by Ángeles Jurado Jiménez." 2009. http://d-nb.info/998103292/34.
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Knowles, Kellen A. "Adipose stromal cells enhance keratinocyte survival and migration in vitro, and graft revascularization in mouse wound healing model." Thesis, 2013. http://hdl.handle.net/1805/3752.
Full textAbstract:
Indiana University-Purdue University Indianapolis (IUPUI)<br>In the US, more than 1 million burn injuries are reported annually. About 45,000 injuries due to fires and burns result in hospitalization and ten percent of these result in death every year. Advances in burn treatment have led to a reduction in mortality rate over the last decades. Since more patients are surviving the initial resuscitation phase even with very large areas of skin being burned away, wound care has become increasingly important to ensure continued patient survival and improvement. While currently a common treatment for third degree burn wounds, skin grafts have several drawbacks. The availability of donor sites for autografts may be limited, especially in incidences of extensive skin loss. The rejection associated with the use of allografts and xenografts may render them inadequate or undesirable. Even if a suitable graft is found, poor retention due to infection, hematoma, and low vascularity at the recipient site are other drawbacks associated with the use of skin grafts as a primary treatment for severe burn wounds. As such, research has been done into alternative treatments, which include but are not limited to artificial skin, cell therapy, and growth factor application. We propose the delivery of adipose derived stem cells (ASC) in combination with endothelial progenitor cells (EC) via Integra Dermal Regenerative Template (DRT) to promote faster graft vascularization and thus faster healing of wounds. Integra DRT is an acellular skin substitute that consists of a dermal layer composed of bovine collagen and chondroitin-6-sulfate glycosaminoglycan, and an "epidermal" layer, which consists of silicone polymer. This silicone layer is removed after the collagen matrix is adequately vascularized (usually takes 2-3 weeks), and then a thin layer autograft is applied to the top of the neo-dermis. ASC are derived from the stromal-vascular fraction (SVF) of adipose tissue and are a readily available, pluripotent, mesenchymal cell known to promote angiogenesis. They are being explored as a treatment for a myriad of diseases and conditions, including wound healing. In combination with ECs, they form stable microvessel networks in vitro and in vivo. In our work, we found that ASC+EC form stable microvessel networks when cultured on Integra DRT. Also, ASC and ASC+EC conditioned media promoted both survival and migration of human epidermal keratinocytes compared to control medium. In a full thickness wound healing model, using healthy NSG mice, the ASC+EC case showed a significantly higher rate of wound closure compared to control. Based on best linear unbiased estimates (BLUE), the difference between the healing rates of ASC alone treatment and the Control treatment group is -0.45 +/- 0.22 mm²/day (p=0.041), which is not less than 0.025 and thus not statistically significant (Bonferroni Adjusted). However, the BLUE for the difference between the ASC+EC group and the Control group healing rates is -0.55 +/- 0.28 mm²/day (p = 0.017<0.025, Bonferroni Adjusted), which is statistically significant. Histology revealed a significantly higher number of vessels compared to control in both ASC alone and ASC+EC case. CD31 staining revealed the presence of human vessels in ASC+EC treatment scaffolds. We conclude that the combination of ASC and EC can be used to accelerate healing of full-thickness wounds when delivered to site of the wound via Integra. This result is especially compelling due to the fact that the mice used were all healthy. Thus our treatment shows an improvement in healing rate even compared to normal wound healing.
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Rhodes, Steven David. "Dissecting the cellular and molecular mechanisms mediating neurofibromatosis type 1 related bone defects." Thesis, 2014. http://hdl.handle.net/1805/3793.
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Indiana University-Purdue University Indianapolis (IUPUI)<br>Skeletal manifestations including short stature, osteoporosis, kyphoscoliosis, and tibial dysplasia cumulatively affect approximately 70% of patients with neurofibromatosis type 1 (NF1). Tibial pseudarthrosis, the chronic non-union of a spontaneous fracture, is a debilitating skeletal malady affecting young children with NF1. These non-healing fractures respond poorly to treatment and often require amputation of the affected limb due to limited understanding of the causative mechanisms.
To better understand the cellular and molecular pathogenesis of these osseous defects, we have established a new mouse model which recapitulates a spectrum of skeletal pathologies frequently observed in patients with NF1. Nf1flox/-;Col2.3Cre mice, harboring Nf1 nullizygous osteoblasts on a Nf1+/- background, exhibit multiple osseous defects which are closely reminiscent of those found in NF1 patients, including runting (short stature), bone mass deficits, spinal deformities, and tibial fracture non-union.
Through adoptive bone marrow transfer studies, we have demonstrated that the Nf1 haploinsufficient hematopoietic system pivotally mediates the pathogenesis of bone loss and fracture non-union in Nf1flox/-;Col2.3Cre mice. By genetic ablation of a single Nf1 allele in early myeloid development, under the control of LysMCre, we have further delineated that Nf1 haploinsufficient myeloid progenitors and osteoclasts are the culprit lineages mediating accelerated bone loss. Interestingly, conditional Nf1 haploinsufficiency in mature osteoclasts, induced by CtskCre, was insufficient to trigger enhanced lytic activity. These data provide direct genetic evidence for Nf1’s temporal significance as a gatekeeper of the osteoclast progenitor pool in primitive myelopoiesis.
On the molecular level, we found that transforming growth factor-beta1 (TGF-β1), a primary mediator in the spatiotemporal coupling of bone remodeling, is pathologically overexpressed by five- to six- fold in both NF1 patients and in mice. Nf1 deficient osteoblasts, the principal source of TGF-β1 in the bone matrix, overexpress TGF-β1 in a gene dosage dependent fashion. Moreover, p21Ras dependent hyperactivation of the Smad pathway accentuates responses to pathological TGF-β1 signals in Nf1 deficient bone cells. As a proof of concept, we demonstrate that pharmacologic TβRI kinase inhibition can rescue bone mass defects and prevent tibial fracture non-union in Nf1flox/-;Col2.3Cre mice, suggesting that targeting TGF-β1 signaling in myeloid lineages may provide therapeutic benefit for treating NF1 skeletal defects.
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Knoch, Bianca. "The effects of dietary eicosapentaenoic acid and arachidonic acid on gene expression changes in a mouse model of human inflammatory bowel diseases : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Nutritional Science at Massey University, Palmerston North, New Zealand." 2010. http://hdl.handle.net/10179/1529.
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Nutrigenomics studies the genome-wide influence of nutrients to understand the association between nutrition and human health. Studies in animal models and humans have demonstrated that dietary n-3 polyunsaturated fatty acids (PUFA) from fish oil may be beneficial in inflammatory bowel diseases (IBD). This thesis aimed to test the hypothesis that dietary n-3 PUFA eicosapentaenoic acid (EPA) reduced and n-6 PUFA arachidonic acid (AA) increased colitis in the interleukin- 10 gene-deficient (Il10–/–) mouse model of IBD, and that these PUFA altered the intestinal bacteria community during colitis development using genome-wide expression and bacterial profiling. Using a combined transcriptomic and proteomic approach, the time-course study defined the onset and progression of colitis in Il10–/– mice. Histopathology, transcript and protein changes before and after colitis onset involved in innate and adaptive immune responses suggested delayed remodelling processes in colitic Il10–/– mice and 11 weeks of age as suitable time point to study the effects of dietary PUFA on colitis development. Comparing the transcriptome and proteome profiles associated with colon inflammation of mice fed with the AIN-76A or oleic acid (OA) diet showed that OA was an appropriate control for unsaturated fatty acids in multi-omic studies. The PUFA intervention study indicated that dietary EPA-induced lipid oxidation might have a potential anti-inflammatory effect on inflamed colon tissue partially mediated through activation of peroxisome proliferator-activated receptor alpha (PPARα). Unexpectedly, dietary AA decreased the expression of inflammatory and stress colonic genes in Il10–/– mice. Altered intestinal bacteria community observed in Il10–/– mice before and after colitis onset was associated with the lack of IL10 protein led to changes in intestinal metabolic and signalling processes. Interestingly, dietary EPA and AA seemed to change intestinal bacteria profiles during colitis development. The role of PPARα in the colon was further examined in a concluding study which identified vanin1 as a likely new PPARα-target gene which may also be involved in lipid metabolism. These findings using a state-of-the-art approach combining transcriptomics, proteomics and physiology provide a basis for future research on molecular mechanisms underlying the effects of dietary PUFA, and might contribute to the development of fortified foods that improve intestinal health and wellness.