Дисертації з теми "Maladies de la vessie – thérapie"
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Biardeau, Xavier. "Optimisation des thérapies de stimulation/modulation électrique dans le traitement des troubles vésico-sphinctériens neurogènes et non-neurogènes." Electronic Thesis or Diss., Université de Lille (2022-....), 2024. http://www.theses.fr/2024ULILS014.
Even if it involves alternating between a filling phase and an emptying phase, the normal micturition cycle cannot be summed up as a binary operation but involves the constant consideration of multiple factors: the filling level of the bladder reservoir, the safety of the environment in which we live, the emotional context in which we evolve and the social constraints to which we are subjected.We now know that there are alterations and/or modifications in brain activity and connectivity, as well as changes in the regulation of the autonomic nervous system, in certain types of lower urinary tract dysfunction - notably in overactive bladder or urge urinary incontinence and in certain types of voiding dysfunctions. Among the therapies available today, electrical modulation/stimulation therapies (tibial neurostimulation and sacral neuromodulation) appear able to normalize and/or modify brain activity and connectivity, as well as ANS balance. They could thus provide at least a partial response to some of the etiopathogenies underlying these lower urinary tract dysfunctions. However, the deployment and positioning of these electrical modulation/stimulation therapies are still limited by an incomplete understanding of their mechanisms of action, imperfect identification of the indications and populations most likely to benefit from these therapies, a lack of consensus on the setting of the electrical current delivered, and a lack of medium and long-term evaluation. In the first part, we questioned the indications for these therapies, and particularly their place as a preventive approach for lower urinary tract dysfunctions due to spinal cord injury. We also questioned the relation, in terms of efficacy, between transcutaneous tibial neurostimulation and sacral neuromodulation, to better support patients in shared medical decision-making processe. Finally, we developed the first tool to predict the success of sacral neuromodulation as a treatment for voiding dysfunction. In the second part, we questioned the mechanisms of action, and more specifically the changes in the balance of the autonomic nervous system in response to an acute S3 sacral root stimulation.In the third part, we questioned the mid-term follow-up (5 years) after definitive implantation of sacral neuromodulation in a geographic population pool, looking for risk factors for discontinuation of follow-up. These data, although still to be supplemented by future research projects, will enable us to further optimize electrical modulation/stimulation therapies in the management of neurogenic and non-neurogenic lower urinary tract dysfunctions
Berrahmoune, Saoussen. "Étude des mécanismes régissant l’efficacité photodynamique sélective de l’Héxylaminolévulinate-Protoporphyrine IX dans le traitement du cancer de la vessie : Application dans le cadre de la prévention de ses récidives." Thesis, Nancy 1, 2009. http://www.theses.fr/2009NAN10012/document.
Photodynamic therapy (PDT) is a treatment modality based on the cytotoxic effect occurring on target tissues by interaction of a photosensitizer with light in the presence of oxygen. The aim of this study was to optimise PDT for treatment and prevention of recurrence of bladder cancer. The study was performed in vivo. PDT was performed with Hexvix® a precursor of the photosentitizer protoporphyrin IX (PpIX). First, we executed a mechanistic analysis of differential PDT effects according to Hexvix® concentration. 8 or 16 mM induced diametrically opposed photodynamic effects. PDT efficacy is depends on the mitochondrial localization of PpIX and its concentration and leads to pro-apoptotic damages. Second, PDT was performed in a rat model mimicking post fluorescence guided TUR. The amount of viable tumor cell within the bladder lumen significantly decreased with PDT and resulted in a significant reduction of tumor implantation
Latourette, Solange. "La thérapie génique." Paris 5, 1994. http://www.theses.fr/1994PA05P100.
Cosserat-Gérardin, Isabelle. "Evaluation expérimentale de la Protoporphyrine IX (PpIX) induite par l'hexylester d'acide 5-aminolévulinique(hALA), et de l'hypéricine pour le traitement photodynamique de tumeurs de vessie." Nancy 1, 2001. http://www.theses.fr/2001NAN11308.
Philippe, Catherine. "Le lavage vésical : un exemple d'application de pharmacie clinique." Paris 5, 1991. http://www.theses.fr/1991PA05P124.
Le, Bacquer Anne-Véronique. "Les complications de la BCG-thérapie endovésicale dans le traitement des cancers superficiels de "la vessie" : revue générale à propos d'un cas." Montpellier 1, 1995. http://www.theses.fr/1995MON11047.
Le, Souder Cosette. "Maladies à prions : vers le développement d'une thérapie génique et cellulaire." Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT051.
Transmissible spongiform encephalopathies are neurodegenerative diseases characterized by a strong vacuolization, a neuronal lost and deposits of prion pathologic protein: PrPSc. This PrPSc accumulation is the result of the conformational conversion of the host encoded endogenous PrPC protein. Although the incidence of these diseases in humans remains low (about one to two cases per million inhabitants per year), these diseases remain a public health problem. Indeed, because of their long and silent incubation period, patients with prion disease may expose people through blood transfusion or organ transplantation with a risk of iatrogenic contamination. In addition, when the diagnosis occurs, brain damage is often massive, and the outcome is always fatal and rapidly occurs. Until now, there is no treatment that could be proposed to patients.The alternative developed by our laboratory for several years, is a strategy of cell therapy coupled with gene therapy. The general objective is to use pluripotent embryonic stem cells (ESC) and graft them as a “medicine” not only to orchestrate a functional recovery of the damaged zones and protect the grafted cells from prion propagation but also to deliver anti-prion molecules.For the anti-prion molecules, we have chosen dominant negative PrP mutants (PrP-DN). Our choice is based on studies showing that a lysine at codon 219 of the human PrP or an arginine at codon 171 of the ovine PrP protect against the development of a TSE. Study of these mutants in infected cells or in transgenic mice showed that the mutated PrPC were not converted into PrPSc. Moreover, they exibit a so-called "dominant negative" protective effect on the conformational conversion of their wild-type PrPC counterparts. A first approach of gene and cell therapy was initiated in the laboratory and has shown encouraging results. Indeed, the graft of murine neural stem cells (NSC) derived from murine embryonic stem cells and expressing anti-prion molecules, has allowed, for some of the mice, to an increase the incubation time of the diseaseas well as to a decrease of astrogliosis and vacuolization.In this context, the first objective of my thesis was to validate the therapeutic approach by showing that the grafted cells were able to inhibit prion replication trough the dominant negative effect of the PrP-DN. To address this point, we have chosen to use an organotypic culture model infected with murine prions (22L strain). In addition to fill the ethical requirements under the European Directive 2010/63 and the 3Rs, organotypic culture models offer the advantage to perform and repeat experiments, kinetic tests, and PrPres analysis. This model also allows to visualize the fate of the grafted cells. Finally, by choosing this strategy, it will be possible to transpose into a humanized model the work previously performed on mouse organotypic cultures.To achieve this task, it was necessary to establish an ex vivo prion model of organotypic culture brain slices, in which it was possible to perform grafts and to evaluate the inhibitory effect of PrP-DN mutants on the prion replication.In addition, as our group is included in the team "Stem cell biology and regenerative medicine" (led by Pr Jorgensen) in which several stem cells are studied (liver stem cells and mesenchymal stem cells (MSC)) and because MSC have been shown to provide protective effects when grafted in the brain of mice with neurological diseases, it was therefore relevant to evaluate the effect of MSC on prion pathology in our prion models and in particular to evaluate the impact of concomitant MSC grafts on NSC-PrP-DN.In a last step, our goal was to transpose the mouse tools (NSC from ES and expressing the PrP-DN mutants) to "human" tools by producing human NSCs derived from human ESC and expressing human PrP-DN, and to characterized the resulted cells
Delmouly, Karine. "Cellules Souches Neurales : modélisation et thérapie cellulaire des maladies à prions." Thesis, Montpellier 2, 2010. http://www.theses.fr/2010MON20134/document.
Transmissible Spongiform Encephalopathies (TSE) are neurodegenerative disorders with long asymptomatic incubation periods and fatal issue. They are induced by accumulation of the pathogen isoform of the prion protein (PrPSc) in the central nervous system (CNS) resulting in neuronal degeneration and astrogliosis. PrPSc, produced by the conversion of the physiological form of the prion protein (PrPC), plays a key role in the disease transmission. The mechanisms underlying the conversion of PrPC and the propagation of PrPSc are uncertain just as the molecular mechanisms giving rise to prion diseases. In the aim of creating or improving cell culture models, it has been shown that CNS Neural Stem Cells (NSC) could support PrPC conversion into PrPSc in vitro. In this project, we used NSC to improve and characterize cellular infection and hypothesized that modification of culture conditions could modulate PrPSc production in NSC. Hence, we used factors known to influence cellular identity in our culture model and showed that higher amount of prions were produced. These models also allow molecular mechanisms studies that could be at infection origin. During the course of this study, we also demonstrated that HEPES added to our culture medium could stop prion propagation in a dose-dependant manner. Moreover, to date no therapy aimed at stopping disease progression has been established in humans. We therefore used NSC with the ultimate goal to elaborate a therapeutic strategy based on the delivery of antibodies into the CNS to block prion replication. These cells will also able to repair damaged brain area thus combining cell and gene therapy
Guttin, Audrey. "Développement d’une bithérapie antitumorale basée sur une approche théranostique : applications aux cancers du cerveau et de la vessie." Thesis, Paris, EPHE, 2016. http://www.theses.fr/2016EPHE3018/document.
Solid malignant tumors have molecular characteristics that clearly distinguish them from healthy tissue. The project is to develop a new therapeutic strategy based on these molecular characteristics. We set up a new therapeutic approach so as to customize treatment by connecting it directly to the diagnosis of the tumor (theranostic approach).Brain tumours and bladder tumours are two examples of particularly aggressive solid tumours. These two types of tumors are classified into several subgroups that have their own molecular profiles. The microRNAs (miR) are molecules naturally synthesized by cells. These molecules may have a role of oncogene or tumour suppressors whose expression is strongly deregulated in tumours. So the assessment of the expression levels of few microRNA allows the distinction of gliomas of high grade compared to low grade.To set up the new therapy we needed to modulate the expression of microRNAs deregulated in tumors. The proposed approach was to counter the expression of oncogenic microRNAs overexpressed using an antimicroARN (antimiR). This type of molecule is chemically similar to the naturally occurring RNA molecules in the cells. For a better efficiency of this new therapeutic strategy, we tried to optimize the transport of the antimiR to increase the therapeutic effect. To vectorize the therapeitic antimiR to the heart of the tumor, we envisioned to chemically combine the antimiR to a cell-penetrating antitumoral compound. Chalcones derivatives which are hydrophobic have this capability. A combination of the two molecules (antimicroARN and chalcone) was evaluated and the results appeared promising
Toupet, Karine. "Stratégies thérapeutiques des maladies à prions." Montpellier 2, 2009. http://www.theses.fr/2009MON20128.
Prion diseases are fatal neurodegenerative disorders that affect both humans and animals. These diseases are induced by the accumulation in the brain of the misfolded isoform of the normal cellular prion protein: PrPSc. The emergence of new risks of transmission for these diseases and the lack of efficient treatments, prompt us to search for new therapeutic strategies and targets. We developed two innovative therapeutic approaches. The first one consisted in searching for molecules able to trap preamyloid forms of PrPSc (dimers and trimers), known as key elements in the replication cycle of prions. A drugs screening approach, in silico and in cellulo, allowed us to discover thienyl pyrimidine and thienyl azine compounds able to specifically oligomerize PrPSc molecules. These PrPSc oligomers decrease prions infectivity in vivo, highlighting the therapeutic potential of these compounds. Our second strategie is a gene therapy approach using the dominant negative properties of certain polymorphisms of the prion protein, such as the Q218K and Q167R mutants. Our objective was to evaluate the therapeutic potential of lentiviral vectors carrying the PrPQ218K and PrPQ167R mutants, in mice, at the terminal stage of the disease. We succeeded in significantly prolonging the survival time of mice of 20%, with two intracerebrally chronic injections of lentiviral vectors carrying the PrPQ167R mutant. All our results not only open the way for new therapeutic strategies against prion diseases but also will benefit for therapies of other neurodegenerative disorders
Bisson, Jean-François. "Application de la thérapie photodynamique sur des tumeurs de vessie induites chez le rat femelle Fischer 344." Nancy 1, 2000. http://www.theses.fr/2000NAN11304.
The number of bladder cancers being in constant progression during the last few years, it is necessary to develop a representative bladder tumor model of human pathology in order to test the validity of new therapeutic methods as photochemotherapy. That's why we created a new bladder tumor model in the female Fischer 344 rat. After performing a local mechanical urothelial denudation, syngenic bladder tumor cells were instilled by uretral way. Development of induced tumors was followed by echography and their nature determined by histopathology. These are infiltrating transitional cell carcinomas with a constant and single localization at the bottom of the bladder and in the axis of uretra. In situ fluorescence spectroscopy, with a miniaturized optic fibers captor, has not allowed to distinguish strictly autofluorescence spectra of the normal bladder and the tumors at the wavelenght used. This non-invasive method has also been used to follow the biodistribution of a photosensitizer (PpIX) after administration by general (intraperitoneal) or local (instillation) route of its precursor (5-ALA) and to determine the maximal tumor/normal bladder ratios. These maximal ratios have been estimated : 2. 85 ± 1. 2 3h30 after intraperitoneal administration and 3. 96 ± 1. 04 after bladder instillation during 4h. These studies were confirmed by fluorescence microscopy, method which also allowed to specify the localization of PpIX according to the time and the 5-ALA administration route used. Finally, we carried out in situ photodynamic treatment of rat bladder tumors with a miniaturized frontal light distributor for the time tumor/normal bladder ratios were maximal. Therapeutic efficacy was defined by histopathological analysis. It was variable according to the infiltrating grade of the tumors but seemed to be independent with the 5-ALA administration route used
Compérat, Eva. "Les évènements moléculaires dans la cancerogènese vesicale." Paris 7, 2006. http://www.theses.fr/2006PA077080.
Urothelial carcinoma (UC) is a frequent cancer, with an incidence of 7800 new cases diagnosed annually in France. These tumors display multifocality and are heterogeneous. Eighty percent are superficial non-invasive neoplasms (pTa) or chorion invasive neoplasms (pTl). Patients with muscle-invasive cancers (pT2) have poor clinical outcome. Bladder carcinogenesis follows a multistep process from dysplasia to carcinoma in situ and bladder wall infiltration. Global analysis of transcriptom is not completely understood. The following studies wanted to gain better insight into the early molecular mechanisms of bladder carcinogenesis, using the real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). We analysed the expression levels of 11 selected genes in bladder spécimen from normal tissue and from different stages in cancer development. Aurora-A involved in mitosis increased in a linear way and was correlated to tumor stage. Five genes showed decreasing levels in cancer: Genes concerning lymphangiogenesis, intercellular adhesion and urothelial differentiation. This study bas been completed by immunohistochemical studies to determine whether expression of these molecules showed correlation to stage and relapse
Volpilière, Marc. "Dysfonctionnement vésico-sphinctérien chez l'hémiplégique vasculaire adulte : à propos de 312 cas." Montpellier 1, 1990. http://www.theses.fr/1990MON11042.
Lesbordes, Jeanne-Claire. "Thérapie génique des maladies motoneuronales par les facteurs neurotrophiques : approches virale et non-virale." Paris 5, 2002. http://www.theses.fr/2002PA05CD06.
Tonnel-Ferroul, Julie. "Complications pulmonaires, hépatiques et ostéoarticulaires consécutives à l'instillation intra-vésicale de B. C. G : à propos de 3 observations." Bordeaux 2, 2001. http://www.theses.fr/2001BOR2M054.
Kowalczuk, Laura. "Applications de l'électrotransfert à l'étude des maladies oculaires inflammatoires et angiogéniques." AgroParisTech, 2010. http://www.theses.fr/2010AGPT0032.
Robert, Florian. "Vers une thérapie pour deux maladies vasculaires rares : criblage de chimiothèques de médicaments pour les maladies Rendu-Osler et Hypertension Artérielle Pulmonaire." Thesis, Université Grenoble Alpes (ComUE), 2019. http://www.theses.fr/2019GREAV039.
BMP9 is a ligand of the TGF-β family and is considered as a vascular quiescence factor. Different actors within BMP9 signaling pathway such as receptors ALK1 and BMPR2 are found to be mutated in two rare vascular diseases, Rendu-Osler disease also called Hereditary Hemorrhagic Telangiectasia and Pulmonary Arterial Hypertension, which are due to endothelial dysfunction. Current treatments aim to improve symptoms in patients, whitout providing a real cure. Thus, it is essential today to find new etiological treatments restoring this signaling pathway. To do this, I used high-throughput screening to reposition potential drug candidates from the Prestwick and TargetMol libraries, a total of 2133 molecules approved by FDA and EMA. These screens were realized on endothelial cells models reporting the BMP9 pathway using a BMP sensitive promoter (BRE, BMP Response Element). I developed and miniaturized a first endothelial model HMEC-1 secreting a BRE-controlled Metridia Luciferase, then a second one using double transfection of Firefly luciferase under BRE control and Renilla Luciferase as a transfection control. The first model revealed only false positives hits. However, the second one allowed us to identify several molecules activating the cAMP pathway but which action hasn’t been confirmed at molecular levels. A last screen was performed on non-endothelial cells (Myoblasts C2C12BRA), allowing us to identify two other molecules which are currently undergoing characterisations
Biot, Claire. "BCG immunotherapy for bladder cancer : characterization and modeling of the bladder immune response to BCG identify strategies for improving anti-tumor activity." Paris 6, 2012. http://www.theses.fr/2012PA066009.
Intravesical instillation of bacillus Calmette-Guérin (BCG) for bladder cancer is one of the few examples of successful immunotherapy in the clinic, though its precise mechanisms of action remain unclear. I established a mouse model to study the dynamics of the immune response following intravesical BCG. I demonstrated that BCG dissemination to bladder draining lymph nodes and T cell priming could occur following a single instillation; yet, repeated instillations with live BCG were necessary for a robust T cell infiltration in the bladder. Subcutaneous immunization with BCG prior to intravesical instillation overcame this requirement, triggering enhanced inflammation, suggestive of a delayed-type hypersensitivity reaction, and accelerating T cell entry into the bladder. Such findings translated into an improved anti-tumor response in mice that were subcutaneously immunized with BCG prior to intravesical treatment of an orthotopic tumor, while analysis of clinical data showed that patients with pre-existing immunity to BCG had significantly longer recurrence-free survival. I also contributed to construct and parameterize a mathematical model describing the interactions between BCG, the immune system, bladder mucosa and tumor cells. The model suggested a requirement for the adaptive immune response to achieve tumor extinction rates similar to the clinic, and helped predict optimal clinical parameters for BCG therapy. Together these data provide new insights into a long-standing clinically effective immunotherapy and predict strategies that may improve patient management, such as the parenteral exposure of patients without immune signature to BCG prior to intravesical therapy
Podevin, Guillaume. "Approche chirurgicale de la thérapie génique in vivo des maladies héréditaires du foie." Nantes, 2006. http://archive.bu.univ-nantes.fr/pollux/show.action?id=51f552e2-17c0-447d-ba36-77190321cf3b.
Ideally, gene therapy for inherited diseases should result in indefinite synthesis of fully active therapeutic protein. Nevertheless, highly efficient gene transfer into hepatocytes in vivo resulted in transient expression of the transgene, due to induction of an immune response against the transgene product. To circumvent this drawback, we developed in rats a surgical approach in which vectors administration was performed through asanguineous perfusion of the liver after complete vascular exclusion. In sight of clinical trial, we also applied surgical techniques of liver perfusion on two large animal models, the lamb and the macaque. Our works demonstrated that: (1) both asanguineous perfusion of the liver together with purification of the viral surpernatant in order to remove soluble transgenic protein were required to decrease significantly immune response, (2) surgical procedures were well tolerated in the two large animal species, and (3) hepatocytes in lamb liver were not easily accessible to viral vectors probably because of thick basal lamina. In conclusion, asanguineous perfusion for in vivo liver gene transfer is a good way to obtain sustained expression of the transgenic protein. Non-human primate is the only relevant model to clearly define the potential of liver gene therapy in clinics
Duque, Sandra. "Thérapie génique des maladies du motoneurone à l'aide de vecteurs dérivés des AAV." Paris 7, 2009. http://www.theses.fr/2009PA077101.
Motor neuron diseases (MND) such as amyotrophic lateral sclerosis (ALS), are incurable degenerative disorders characterised by the selective loss of motor neurons (MNs) localised in the motor cortex, the brainstem and/or the spinal cord. To date, there is no treatment for these disorders because of the blood brain barrier (BBB) which hindered the crossing of the therapeutic molecules from the circulation flow to the central nervous System (CNS) parenchyma. New therapeutic strategies, based on gene transfer using viral vectors have thus been developed. This study aimed to evaluate new strategies for increasing the efficiency of MNs transduction using AAV vectors. The fîrst approach bypasses the problem of the BBB by injecting the viral vectors directly into brain areas at the origin of the descending spinal pathways. The injection of AAV vectors expressing therapeutic transgenes into these specific brain structures could indeed lead to the production and traffîcking of therapeutic proteins through descending pathways to the spinal cord by anterograde axonal transport mechanisms. The subsequent secretion of these proteins could thus influence the survival and the activity of the spinal cord MNs. The second approach is based on the systemic administration of a new serotype and genome AAV vectors, the self-complementary AAV9 vector. We identifîed the remarkable ability of AAV9 vectors to transduce cells of the CNS, including MNs, after a single intravenous injection in adult mice. This gene transfer strategy represents an efficient and non-invasive procedure to reach the CNS. This result raises thus great hopes for the treatment of MN disease and other neurological disorders
Ribault, Sébastien. "Thérapie génique des maladies cardiovasculaires Ciblage transcriptionnel des vecteurs de transfert de gènes." Université Louis Pasteur (Strasbourg) (1971-2008), 2001. http://www.theses.fr/2001STR13206.
Coyat, Carolanne. "Mécanismes moléculaires responsables de neuropathies auditives et thérapie." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT080.
The objective of my thesis was based on the identification of the cellular and molecular mechanisms that cause deafness associated with ODA. To do this I used a mouse model carrying a mutation commonly identified in OOD patients (OPA1 of delTTAG). I combined functional, morphological and molecular approaches to identify the links between the OPA1 mutation of the TTAG and mitochondrial dysfunction, oxidative stress and DNA damage and hearing loss. Elucidating these mechanisms would make it possible to consider new therapeutic targets to prevent the degeneration of cochlear cells linked to mutations in the OPA1 gene
Gurram, Venu. "Preuve de principe pour la thérapie de l'atrophie optique dominante de type1." Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30215.
The impact of visual handicaps has dramatically risen with the contemporary means of visual communication. A major cause of visual impairment lies in optic nerve atrophies often due to defects in mitochondria. Mutations in the gene coding for the mitochondrial protein OPA1 lead to the main form of Dominant Optic Atrophy (DOA), due to degeneration of the Retinal Ganglionic Cells (RGCs), which axons form the optic nerve. OPA1 is involved in the fusion of mitochondria, which together with mitochondrial fission determines the morphology of mitochondria, allows their immediate adaptation to energetic needs and controls their quality by restoring or removing damaged organelles. In addition, OPA1 has other functions including mitochondrial DNA maintenance and protection from apoptosis. To date, there is no therapy available for DOA. My thesis aimed at developing both genetic and pharmacological therapeutic strategies for this disease. Genetic strategy involved the expression of a protein called X from the Borna Disease Virus, which was shown to have neuroprotective properties in in vitro and mouse model of Parkinson Disease by D. Dunia's team. Work in P. Belenguer 's team has shown that X rescued the defects in mitochondrial morphology, dendritic arborisation and synapses induced by downregulation of OPA1 in primarily cultured neurons. In continuation, I showed that X rescued the defects in mitochondrial morphology of fibroblasts of DOA patients harbouring OPA1 mutations by inducing mitochondrial elongation. On the other hand, as part of pharmacological therapy, P. Belenguer's team recently showed that two repurposed drugs, clomiphene and hexestrol, rescued mitochondrial defects in yeast mutated for the orthologue of OPA1. I extended the study to the mammalian system, by analysing the effect of the two drugs on mitochondrial morphology in DOA fibroblasts bearing OPA1 mutations. I showed that the two the drugs rescued defects in mitochondrial morphology by inhibiting the fission process. Although, this project aimed to extend the analysis of the effect of X protein as well as of hexestrol and clomiphene, in vivo, unfortunately, I was not able to evidence the previously described retina and optic nerve defects in a DOA mouse model, impairing its use to test the protective effect of X and the two drugs. In conclusion, although, these pre-clinical studies need to be extended in vivo, the results in vitro indicated that the two genetic and pharmacological strategies could be effective to treat DOA. To my knowledge, this work is first of its kind, where mitochondrial dynamics, i.e. the equilibrium between mitochondrial fusion and fission, was targeted to treat DOA disease. Furthermore, this work is also giving the hope to develop therapies for other RGCs associated mitochondrial diseases like Leber Hereditary Optic Neuropathy and glaucoma
Amsellem-Ouazana, Delphine. "Implications de la voie de signalisation ERBB dans la carcinogénèse urothéliale." Paris 5, 2006. http://www.theses.fr/2006PA05N13S.
ERBB-driven growth pathway has been implicated in most human epithelial malignancies including transitional cell carcinoma (TCC) of the bladder. Using quantitative real-time RTPCR we showed the interest of simultaneously quantifying the mRNA expression levels of the four ERBB and their eleven ligand genes in a series of bladder TCC. We were able to show an excellent correlation between TT-PCR results and immunohistochemistry for the evaluation of ErbB2 overexpression. We also confirmed that in bladderTCC,ERBB2 gene amplification only accounts for a small number of protein
Detante, Olivier. "Thérapie cellulaire par cellules souches mésenchymateuses humaines après ischémie cérébrale." Grenoble, 2010. http://www.theses.fr/2010GRENV008.
Stroke is the leading cause of acquired adult disability. Improving brain plasticity after stroke represents an important therapeutic strategy. Cell therapy favours functional recovery after cerebral ischemia in rodent models. The pioneer clinical studies did not reproduce this benefit for patients due to a limited number of studied patients. Ln our preclinical studies, we observed a good tolerance and a functional benefit of the intracerebral (at the acute phase) and intravenous (IV) (at the subacute phase) administration of clinical-grade human mesenchymal stem cells (hMSC). The hMSC survival (during several weeks) and their differentiation into neurons or astrocytes are very limited and can not explain alone the functional benefit. Among different mechanisms of action of hMSC (neurotrophic and/or proangiogenic effects, immunomodulation. . . ), we showed by MRI an early microvascular effect. We also showed that hMSC can be labeled for MRI and microscopy by iron microparticles without altering cell properties. This cell labeling is useful to detect and follow hMSC grafted into the brain but is insufficient to follow the IV injected hMSC. To assess the biodistribution ofIV injected hMSC, we conducted a nuclear imaging study. This experiment showed that the hMSC are attracted to cerebral ischemic lesion in the first hours following their injection. Ln paraIlel, we developed a phase 2 clinical trial. We do not know yet the best route of administration, the best dose and the optimal delay of the graft. The cell therapy optimization needs the development of translational projects with experimental studies linked to clinical trials. Thus cell therapy could become an efficient treatment for stroke
Delesse, Labe Marie-Dominique. "Les complications pulmonaires et générales de l'immunothérapie intravésicale par le BCG dans les tumeurs superficielles de la vessie : à propos d'un cas." Nancy 1, 1990. http://www.theses.fr/1990NAN11038.
Magy, Laurent. "FGF2 et myelinisation : vers une stratégie de thérapie génique ex vivo des maladies demyelinisantes." Paris 6, 2003. http://www.theses.fr/2003PA066201.
Salgues, Frédéric. "Ciblage des lysosomes pour la thérapie enzymatique substitutive ou pour la thérapie photodynamique." Thesis, Montpellier 2, 2011. http://www.theses.fr/2011MON20148.
The cation independent mannose-6-phosphate receptor (CI-M6PR) allows the endocytosis and the transfer of molecules bearing the M6P marker to lysosomes. To improve both the affinity for the CI-M6PR and stability of the M6P residue, we carried out the synthesis of isosteric M6P analogues functionalized at the anomeric position to allow efficient coupling to molecules of therapeutic interest. First, the coupling on human recombinant enzymes was performed. The remodelling of the oligosaccharide part of the lysosomal enzyme GAA, whose deficiency is responsible for Pompe disease, helped to highlight the neoglycoGAA is recognized efficiently by CI-M6PR and its enzymatic activity is completely preserved. Second, the coupling of these analogues of M6P to porphyrins for photodynamic therapy of cancer was considered. The model developed in the mannose series has validated our strategy of ligation of saccharides to photosensitizers. The employed methods avoid the conventional steps of deprotection of saccharides after coupling. The biological study with the prepared glycosylporphyrins demonstrated the photoinduced cytotoxicity
Leclercq, Sabrina. "Régulation du gène Abcd2 de rat dans le cadre d’une thérapie pharmacologique de l’Adrénoleucodystrophie liée au chromosome X." Dijon, 2007. http://www.theses.fr/2007DIJOS018.
X-ALD is a neurodegenerative disorder caused by mutations in the ABCD1 gene which encodes a peroxisomal ABC half-transporter called ALDP. ALDRP, encoded by ABCD2, is the closest homolog of ALDP and displays a partial functional redundancy, when overexpressed, and is considered as a potential therapeutic target for X-ALD. In this work, we show that the Abcd2 basal expression is more important in female rat liver than in male. This regulation may involve the PRE half-site present in the Abcd2 5’UTR promoter, progesterone and its receptor. Moreover, the Abcd2, Abcd3 and Abcd4 relative expression is more important in male rat liver fed a diet without α-linolenic acid than in male rat liver fed a diet containing this fatty acid. On the contrary, Abcd1 relative expression is more important in the liver of male rat fed a diet containing α-linolenic acid than a diet without α-linolenic acid
Baldeschi, Christine. "Epidermolyse bulleuse dystrophique : étude préclinique de thérapie génique et implication du collagène VII dans la tumorigénèse." Nice, 2004. http://www.theses.fr/2004NICE4050.
Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited skin disorder caused by mutations in collagen VII. RDEB is characterized by skin blistering, abnormal healing, contractures and cancers. No conventional therapy is available for this disease, which justifies the perfection of treatments based on gene therapy. Our challenge was the isolation of highly clonogenic RDEB keratinocytes, the successful and efficient transfer of the large-size collagen VII cDNA (9kb) and the reconstruction of transplantable skin equivalents made with genetically modified cells from human and dog RDEB patients. This research is currently in progress and it implies preclinical assays on the RDEB dogs to validate the gene therapy approach for the treatment of the condition. In RDEB, absence or abnormal expression of collagen VII results in aggressive squamous cell carcinomas. Primary RDEB keratinocytes display altered migration and invasion properties ex vivo, which indicates a possible proneness to tumor progression. These properties have been associated to an increased of the expression of the metalloproteinases MMP1 and MMP3. Interestingly, expression of collagen VII in transduced RDEB keratinocytes strongly down regulated the expression of MMP1 and MMP3. All together, our result shows that collagen VII plays a major role of invasive suppressor by down regulating MMP1 and MMP3 expression in keratinocytes
Bouaita, Aïcha. "Essais de thérapie génique contre la dégénérescence rétinienne chez la souris Harlequin déficiente pour la protéine mitochondriale AIF." Paris 6, 2012. http://www.theses.fr/2012PA066566.
Biot, Claire. "BCG-THERAPIE ET CANCER DE LA VESSIE : LA CARACTERISATION ET LA MODELISATION DE LA REPONSE IMMUNE AU BCG DANS LA VESSIE REVELENT DES STRATEGIES POUR L'AMELIORATION DE LA REPONSE ANTI-TUMORALE." Phd thesis, Université Pierre et Marie Curie - Paris VI, 2012. http://tel.archives-ouvertes.fr/tel-00827698.
Moulay, Gilles. "APPROCHES DE THÉRAPIES GÉNIQUES POUR DES MALADIES NEUROMUSCULAIRES." Phd thesis, Université d'Evry-Val d'Essonne, 2010. http://tel.archives-ouvertes.fr/tel-00507450.
Lavallée, Alexandre. "La philosophie de Nietzsche comme thérapie." Thesis, Université Laval, 2012. http://www.theses.ulaval.ca/2012/29442/29442.pdf.
Couet, Lydia. "Soigner la folie et collectionner 'l'art des fous' : l'art asilaire au XIXème siècle : archéologie de l'art brut." Thesis, Bourgogne Franche-Comté, 2019. http://www.theses.fr/2019UBFCH030.
Treating madness and collecting the "art of the insane". Asylum art during the nineteenth century : an archeology of Art Brut.This work is about artifacts made by patients in asylums during the XIXth and the beginning of the XXth century: from their entrance into scientific collections and publications, until the first exhibitions into art galleries during the 1920's. We will try to show how, thanks to the role of some personalities of medical, litterary and artistic areas, the medical status of those creations will be overtaken and they will begin to invest artistic scene
Haase, Georg. "Thérapie génique de maladies dégénératives des motoneurones et transfert de gènes dans le nerf lésé." Paris 5, 1999. http://www.theses.fr/1999PA05CD05.
Leblond, Anne-Laure. "Thérapie cellulaire des maladies respiratoires : utilisation de la voie aérienne pour l'implantation de cellules souches." Nantes, 2008. https://archive.bu.univ-nantes.fr/pollux/show/show?id=94d92b74-c5e4-4ca9-8688-0e2e42a8e3e2.
Over the past decade, interest has increased in the use of stem cells from bone marrow to optimize lung repair after systemic administration in irradiated mice. These studies lead to limited and controversial results because of fluorescent detection methods. The objective of our work was to develop a stem cell based strategy while avoiding animal irradiation and controversial detection methods. Embryonic and mesenchymal stem cells were intratracheally injected in a murine model with acute epithelial airway injury. Epithelial injury was induced by intratracheal detergent administration. Quantitative methods showed that 0. 4 to 5. 5% stem cells survived specifically in the injured airway, whereas no differentiated cells survived in injured airway. Importantly, stem cells did not survive in healthy airway. With biochemical staining, mesenchymal stem cells were detected in injured trachea lumen and bronchi. 7 days after detergent administration while airway epithelium was totally repared, stem cells were located in regenerated bronchia. With this experimental design, we demonstrated the feasibility of intratracheal cell delivery for airway diseases with acute epithelial airway injury
Labrande, Christelle. "Neuroprotection et thérapie cellulaire : deux approches expérimentales dans le traitement des accidents vasculaires cérébraux ischémiques." Aix-Marseille 2, 2007. http://www.theses.fr/2007AIX22959.
Lostal, William. "Approches thérapeutiques pour le traitement des dysferlinopathies." Thesis, Evry-Val d'Essonne, 2010. http://www.theses.fr/2010EVRY0009/document.
In this work, I developed and studied therapeutical strategies for dysferlinopathies, neuromuscular disorders due to dysferlin deficiency. To date, no treatment is available for these diseases. We generated and characterized a dysferlin deficient mouse model, B6.A/J-Dysfprmd. The onset begins at 2-month old with an associated decrease of locomotor activity. For gene transfer approach into muscle, dysferlin coding sequence is too large to enter into a single rAAV. We used properties of rAAV to concatemerize by ITR sequences interaction. Results, obtained with this strategy, showed expression of entire dysferline protein until at least one year. We showed also that this expression is associated to an improvement of phenotype and functional activity of tretaed mice. We also studied therapeutical potential of a truncated dysferlin protein. Results showed the expression of a short protein cassociated to a partial functional membrane repair activity, but none in locomotor activity. Nonetheless, these results showed for the first time a partial modularity of dysferlin. Finally, we also studied compensation of dysferlin by myoferlin overexpression in muscle. A myoferlin-overexpressing transgenic mouse model was generated; a significant level of myoferlin is detected but no deleterious effect was observed. These transgenic mice were crossed with dysferlin deficient mice. An improvement of membrane repair capacity is observed, nevertheless, dystrophic features into muscle were still present
Junges, Martine. "P. U. V. A. Thérapie : de la photobiologie cutanée aux applications en dermatologie." Nancy 1, 1996. http://www.theses.fr/1996NAN10085.
Jacobin-Valat, Marie-Josée. "Nouvelles perspectives pour le diagnostic et la thérapie des pathologies myocardiques et thrombotiques : obtention d'anticorps monoclonaux humains recombinants." Bordeaux 2, 2001. http://www.theses.fr/2001BOR28853.
Scintigraphic studies of myocardial pathologies and the treament of Acute Coronary Syndrome (ACS) show the necessity to obtain a new class of agents that could be injected in humans without provoking the immune system. It's the reason why we chose to study the diagnostic and therapeutic potential of human mAbs. The ability of a monospecific human IgM Mab (B7) obtained by the research team, to bind to human heart myosin suggests that this mAb may be useful in the imaging of mycordial necrosis after myocarditis of graft rejection. Owing to the fact that the parent molecule is an IgM, the scFv fragment were constructed by molecular ingineering to alleviate problems such as a poor diffusion and a slow penetration inside necrotic myocytes. For a purpose of detection of newly formed thrombi, we determined the feasibility of imaging thrombi using a 123-I labeled murine Mab XIIF9 in an atherosclerotic rabbit model of acute arterial thrombosis. This Mab presented with high affinity and specificity for αIIbβ3 expressed on activated platelets holds promise for ACS imaging. Moreover, we have made a great deal of efforts towards developping αIIbβ3 inhibitors that block fibrinogen inducing platelet aggregation and have a more significant impact for therapeutic management of patients with ACS than currently used αIIbβ3 antagonists. We have succeeded in generating three libraries of single-chain antibodies (TE, EB and BO) from the B cells of patients with Glanzmann's Thrombasthenia or AutoimmuneThrombocytopenic Purpura developing in their sera antibodies against the αIIbβ3 integrin. We obtained several specific recombinant phage-antibodies stemmed from studied patients by phage display of single-chain antibodies on the surface of filamentous phage, some of them recognising the activated form of the integrin. A first important conclusion issuing from our results is that the immune reaction occurring during these diseases consists of a polyclonal hypermutations displayed in the complementarity-determining regions by anti-αIIbβ3 fragments supports the hypothesis of the pathogenesis of developing antibodies. Thirdly, CDR3H analysis of phage-antibodies points out recurrent patterns. Affinity studies and assays for inhibition of platelet aggregation clearly show the therapeutic potential of some of these recombinant antibodies
Masse, Florence, and Florence Masse. "Développement de nouveaux vecteurs de médicaments à base de nanoparticules d'or pour la thérapie oculaire." Master's thesis, Université Laval, 2019. http://hdl.handle.net/20.500.11794/37628.
Le traitement de maladies oculaires par voie topique est simple pour le patient. Il est préconisé dans plus de 90% des cas puisqu’il est généralement moins invasif que les traitements alternatifs. Cependant, l’efficacité des médicaments administrés par voie topique demeure limitée en raison de processus physiologiques qui entraînent une faible absorption. Les travaux réalisés au cours de cette maîtrise visent l’amélioration de la biodisponibilité des médicaments pour la thérapie oculaire grâce à un vecteur à base de nanoparticules d’or. L’intérêt de l’utilisation des nanoparticules d’or comme vecteur consiste à utiliser leurs propriétés mucoadhésives afin d’augmenter le temps de rétention des médicaments à la cornée, et ainsi, d’en permettre une plus grande absorption. Ce projet se divise en cinq volets. Le premier volet vise l’étude des connaissances actuelles sur les nanoparticules d’or en ophtalmologie, et souligne les caractéristiques qui mènent à la synthèse de nanoparticules non-toxiques. Le deuxième volet présente l’évaluation des propriétés mucoadhésives des nanoparticules d’or. Cela implique d’évaluer leur affinité pour les mucines, soit des protéines du film pré-cornéen. Afin d’obtenir des nanoparticules pouvant supporter les conditions nécessaires à leur usage in vivo, la synthèse et la caractérisation de nanoparticules d’or ultrastables ont été réalisées. L’optimisation de l’encapsulation de médicaments dans la couronne périphérique de la nanoparticule constitue le quatrième volet. Finalement, l’étude de la cytotoxicité des nanoparticules d’or représente le cinquième volet. Les expériences ont démontré que nos nanoparticules d’or mucoadhésives et ultrastables supportent des conditions drastiques, dont l’autoclave, permettant leur stérilisation pour des usages in vivo. Des molécules actives utilisées en thérapie oculaire peuvent y être encapsulées. De plus, les nanoparticules ne semblent pas affecter les mécanismes biologiques. Ces données suggèrent l’amélioration potentielle de la thérapie oculaire grâce aux nanoparticules d’or.
Topical ocular therapy is a simple administration route used in more than 90% of cases when a patient need ocular treatment. It is generally less invasive than other available treatments which often involve intraocular injections and puncture wounds. However, efficiency of active molecules administered topically is limited considering that less than 0.02 % is successfully absorbed by the cornea. This master’s project aims the amelioration of ocular therapy by enhancing biodisponibility of active molecules thanks to a drug vector based on gold nanoparticles. Gold nanoparticles present mucoadhesive properties, leading to the increase of the retention time of drugs at the cornea, thus enhancing their absorption. This project is divided in 5 aspects. The first aspect aims to overview the actual knowledge on gold nanoparticles in ophthalmology and to highlight synthesis parameters leading to non-toxic nanoparticles. Second part presents the evaluation of gold nanoparticles’ mucoadhesive properties, which imply the evaluation of their affinity for pre-corneal film proteins, as mucins. To be used in vivo , gold nanoparticles must support sterilization, formulation treatments as well as physiological media. Third aspect presents the synthesis and characterization of ultrastable gold nanoparticles. Their capacity to encapsulate active molecules within their polymeric crown is evaluated as the fourth aspect. Finally, as the fifth aspect, the cytotoxicity of the nanoparticles was evaluated. The mucoadhesive ultrastable gold nanoparticles support drastic conditions, as autoclave sterilization predicting their use in vivo. Active molecules were successfully encapsulated within their ligands. Furthermore, they do not seem to cause any alteration of biological mechanism in cells. These results suggest potential improvement of ocular therapy thanks to gold nanoparticles.
Topical ocular therapy is a simple administration route used in more than 90% of cases when a patient need ocular treatment. It is generally less invasive than other available treatments which often involve intraocular injections and puncture wounds. However, efficiency of active molecules administered topically is limited considering that less than 0.02 % is successfully absorbed by the cornea. This master’s project aims the amelioration of ocular therapy by enhancing biodisponibility of active molecules thanks to a drug vector based on gold nanoparticles. Gold nanoparticles present mucoadhesive properties, leading to the increase of the retention time of drugs at the cornea, thus enhancing their absorption. This project is divided in 5 aspects. The first aspect aims to overview the actual knowledge on gold nanoparticles in ophthalmology and to highlight synthesis parameters leading to non-toxic nanoparticles. Second part presents the evaluation of gold nanoparticles’ mucoadhesive properties, which imply the evaluation of their affinity for pre-corneal film proteins, as mucins. To be used in vivo , gold nanoparticles must support sterilization, formulation treatments as well as physiological media. Third aspect presents the synthesis and characterization of ultrastable gold nanoparticles. Their capacity to encapsulate active molecules within their polymeric crown is evaluated as the fourth aspect. Finally, as the fifth aspect, the cytotoxicity of the nanoparticles was evaluated. The mucoadhesive ultrastable gold nanoparticles support drastic conditions, as autoclave sterilization predicting their use in vivo. Active molecules were successfully encapsulated within their ligands. Furthermore, they do not seem to cause any alteration of biological mechanism in cells. These results suggest potential improvement of ocular therapy thanks to gold nanoparticles.
Lemarchand, Patricia. "Thérapie génique des maladies respiratoires : Transfert de gènes par voie vasculaire à l'aide de vecteurs adénoviraux." Paris 5, 1995. http://www.theses.fr/1995PA05CD01.
Cano, Jean-Pierre. "Dysfonctionnement vésico-sphinctérien et hémiplégie vasculaire de l'adulte : à propos de l'analyse de 245 hémiplégies." Montpellier 1, 1989. http://www.theses.fr/1989MON11232.
Harnafi, Hicham. "Etude de l'effet des composés bioactifs du basilic sur le métabolisme lipidique et la péroxydation des lipoprotéines de basse densité." Lille 2, 2008. http://www.theses.fr/2008LIL2S016.
Nguyen-Khac, Eric. "Maladie alcoolique du foie : génétique, diagnostic, et thérapeutique." Amiens, 2008. http://www.theses.fr/2008AMIED006.
Mahieu-Caputo, Dominique. "Les hépatocytes foetaux, vecteurs potentiels de thérapie cellulaire des maladies hépatiques. Transplantation chez l'adulte et in utero." Paris 5, 2004. http://www.theses.fr/2004PA05N048.
Transplantation of hepatocytes is a promising approche for the treatment of severe liver disease. The hurdles faced with adult hepatocytes could be surmounted with the use of human fetal hepatoblasts. Intra-uterine transplantation could improve chimerism and avoid termination of pregnancy in case of prenatal diagnosis. Primate fetal hepatocytes can be isolated, cryopreserved and immortalized. In utero allo-transplantation is feasible, allowing for short-term detection of donor hepatocytes. We have isolated, characterized,transduced and cryopreserved hepatoblasts from human livers at an early stage of development (11-13 weeks of gestation). After transplantation, cryopreserved cells engrafted into the liver of athymic mice for long term (12 sem), proliferated(up to 10% repopulation) and matured expressing Alb, Alpha-1-Antitrypsin, Cytochrome P450.
Cheikh, Khaled El. "Synthèse et évaluation biologique d’analogues du mannose 6-Phosphate fonctionnalisés pour la thérapie enzymatique substitutive." Montpellier 2, 2009. http://www.theses.fr/2009MON20089.
Lysosomal storage diseases are a group of 50 genetically inherited disorders that are characterized by a deficiency of one or more specific lysosomal enzymes which causes an accumulation of substrates inside the lysosome. Enzyme replacement therapy consists in the targeting of recombinant enzymes through the cation-independent mannose 6-phosphate receptor (CI-M6PR) transport. CI-M6PR allows the transport of enzymes carrying the M6P marker towards the lysosomes. The main drawback with the M6P recognition marker is its sensitivity to hydrolysis by phosphatases. Therefore, isosteric analogues of M6P functionalized at the anomeric position by different spacer arms were synthesized. The biological evaluation of these analogues revealed that they are stable in human serum and are recognized by CI-M6PR as well as the M6P itself. Additional studies on living cells showed that none of the prepared analogues is cytotoxic. The conjugation of AMFA-1 to the cathepsin D-KDEL low affinity mutant induced a 10-fold increase of its affinity for the CI-M6PR. The enzymatic activity of chemically modified cathepsin D-KDEL was found fully maintained
Pryadkina, Marina. "Développement d’approches thérapeutiques pour le traitement des dysferlinopathies." Thesis, Evry-Val d'Essonne, 2014. http://www.theses.fr/2014EVRY0039.
The dysferlinopathies are a group of untreatable progressive muscular dystrophies, caused by absence or deficiency of the sarcolemmal protein, dysferlin, as a consequence of mutations in DYSF gene. Recombinant adeno-associated virus (rAAV) is currently the most appropriate vector for gene delivery into the skeletal muscle. However, the ~5kb packaging size of this virus is a major obstacle for large gene transfer like dysferlin. To overcome this limitation, several strategies were developed. Firstly, several modular dysferlins (minigene) having a size of about 4.7kb were created and tested, in order to look for: role of specific domains in the toxicity and the function, the interactions with the partners and the therapeutical potential. It was demonstrated, that the restoration of the membrane repair deficit is not sufficient to improve the muscle histology; that the DYSF domain can be responsible for the toxicity and that the domain FER interacts with the protein OPTN. Secondly, several large gene transfer techniques: concatemerization-splicing, overlapping vectors, hybrid dual or fragmented AAV, were compared to deliver the DYSF gene into the skeletal muscle by two rAAV vectors. The rAAVs intramuscular injections into dysferlin deficient mice showed that the overlap strategy is the most effective approach to reconstitute a full-length messenger. The systemic administration of overlapping vectors was efficient to correct the histopathology and resistance to eccentric contractions of muscular fibers in the dysferlin deficient mice. These data indicate that using overlapping vectors could be a promising approach for a potential clinical treatment of dysferlinopathies
Kopf, Heidrun. "Application à la gestion du stress d'une pychothérapie cognitive et comportementale : mise au point d'un programme spécifique destiné aux patients cardio-vasculaires." Besançon, 2000. http://www.theses.fr/2000BESA1024.