Dissertationen zum Thema „Mutation gain de fonction“
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Berrabah, Sofia. „Etude de nouvelles cibles thérapeutiques dans les lymphomes compliquant la maladie cœliaque“. Electronic Thesis or Diss., Université Paris Cité, 2021. http://www.theses.fr/2021UNIP5201.
Der volle Inhalt der QuelleRefractory coeliac disease type II (RCDII), also called intraepithelial lymphoma, is a rare but severe complication of coeliac disease characterized by the clonal expansion of a small subset of innate intraepithelial lymphocytes (IEL), present in the normal human and murine intestine. Our lab has shown that this population displays shared features between T and natural killer (NK) cells. These so-called iCD3+ innate IEL are mainly characterized by intracellular expression of CD3, which is not detected at the cell surface, expression of NK receptors as well as DNA rearrangement of T cell receptor genes. Our lab has also shown that iCD3+ innate IEL originate from bone marrow precursors through coordinated NOTCH1 and interleukin (IL)-15 signals. During lymphomagenesis, iCD3+ innate IEL of most RCDII patients were shown to have acquired somatic gain-of-function mutations in JAK1 and/or STAT3 that confer increased sensitivity to interleukin-15, a cytokine overexpressed in the intestine of coeliac patients, thereby promoting their clonal expansion. Thus, our hypothesis is that JAK1/STAT3 mutations play a key role in initiating lymphomagenesis associated to coeliac disease in an IL-15-rich environment and that they could represent an attractive therapeutic target.The first objective of my thesis was to study the interest of JAK/STAT inhibitors for RCDII treatment. First, we have tested in vitro different JAK/STAT inhibitors on IL-15-dependent RCDII or normal IEL-T cell lines. We have shown that these inhibitors decrease the proliferation and phosphorylation of STAT3 and increase cellular apoptosis in both RCDII and normal T cell lines. Secondly, we have established a xenograft model based on the injection of cells derived from biopsy or blood from one RCDII patient into immunodeficient mice overexpressing the human IL-15 transgene in their gut epithelium (Rag-/-Gc-/- IL-15TgE; IRGC) to test the efficacy of JAK/STAT inhibitors in vivo. Treatment of xenografted mice with ruxolitinib, a potent inhibitor of JAK1/JAK2 decreased the frequency, number and cytotoxic potential of human tumoral cells and allowed clinical restoration. These preliminary results are encouraging but need to be confirmed. The second objective of my thesis was to test whether the Stat3 pD661V mutation is sufficient to induce the intraepithelial lymphoma in an IL-15-rich context in IRGC mice. We have successfully generated murine iCD3+ innate IEL in vitro, resembling their human counterparts from common lymphoid precursors by combining NOTCH and IL-15 signals. We then transduced CLP with a retroviral vector containing wild-type or mutated Stat3 pD661V. The transduced cells were injected into IRGC mice that subsequently were followed-up during a period of 8 weeks. In vitro generated iCD3+ innate IEL preferentially homed to the intestine. However, no development of intraepithelial lymphoma was observed suggesting that the Stat3 pD661V variant alone is not sufficient to induce the intraepithelial lymphoma. These preliminary results need to be reproduced and confirmed. The murine model used to test the role of STAT3 will now be used to evaluate the respective contribution of canonical mutations in JAK1 and STAT3 and of other recurrent mutations identified in RCDII
Plaud, Clément. „Mécanismes moléculaires et cellulaires des paraplégies spastiques héréditaires liées aux mutations du gène SPG4 : haploinsuffisance VS gain de fonction pathologique“. Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLE037/document.
Der volle Inhalt der QuelleCentral motor neurons are specialized cells involved in the control of voluntary movements in human. The transmission of information along the axon of these neurons is comparable to car trafficking in a highway: information travel in both direction and sometimes traffic jam events occur. When the transit of information are slowed or impaired, patients may suffer of neurodegenerative diseases as hereditary spastic paraplegia (HSPs). In this thesis we investigated the role of spastin, a protein implicated in HSP and the maintenance of these highways. Our results showed that depletion of spastin, or expression of its mutants, lead to a disturbance of both the integrity of these « road » and the traffic of cellular components primary involved in axonal survival and growth. These results would help to elucidate the pathophysiological mechanisms implicated in the onset of this pathology and maybe in developing proficient therapeutic strategy for HSP patients
Jiang, Dadi. „Analysis of a p53 Gain-of-function Mutation in Transgenic Mouse Salivary Tumors“. VCU Scholars Compass, 2007. http://scholarscompass.vcu.edu/etd_retro/103.
Der volle Inhalt der QuelleLartigau, Jérôme. „Le contrôle de gestion à l’heure des réformes hospitalières : une fonction en mutation ?“ Thesis, Montpellier 1, 2010. http://www.theses.fr/2010MON10036/document.
Der volle Inhalt der QuelleCaught between a continuous rise in spending and a stagnation of their financial resources, public hospitals have long been faced with a problem of managing scarcity. To address this problem, many of them have implemented management control, with the difficulties of such an approach in an organization traditionally described as "professional." From the beginning mainly oriented toward expenditure control, management control in hospitals is undergoing a deep challenge with the advent of prospective payment system and the implementation of clinical directorates. Now the management control function should no longer be confined to this role which was traditionally recognized, but must actively contribute to the enhancement of the hospital's revenue. This new dynamics - which gives greater importance to fundamental concepts of management control - is innovative because of the importance it gives to producers of medical activity. The mutation of the management control function in the hospital sector is a major phenomenon for practitioners but is also particularly from a theoretical point of view. It challenges the traditionally accepted representations of management control in the hospital organization and gives an opportunity for researchers to use new theoretical frames
Alouche, Nagham. „Impact d’un gain de fonction de CXCR4 sur la différenciation et la biologie plasmocytaire“. Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS450.
Der volle Inhalt der QuelleCXCR4 plays an essential role in B cell development and controls partially plasma cell (PCs) homing to the bone marrow (BM). Heterozygous gain-of-function mutations of CXCR4 affecting its desensitization in response to the chemokine CXCL12 have been reported in a severe immune-deficiency disorder called WHIM syndrome (WS) and recently identified in Waldenström’s macroglobulinemia (WM), a B lympho-plasmacytoma characterized by the expansion of proliferative clonal malignant lymphoplasmacytic cells which secrete IgM Abs and mainly persist in the BM. Here we used a unique knock-in mice harboring the mutation Cxcr4+/1013 previously described in patients to assess how a gain-of-Cxcr4-function impacts PC biology and antibody (Ab) production. Following vaccination, WS patients mount a normal immune response but fail to maintain Ab titers over time. Therefore, the first part of my PhD was focused on studying the T-dependent humoral response in Cxcr4+/1013 mice. We showed that a strong reduction of antigen (Ag)-specific long-lived PCs in the BM of Cxcr4+/1013 mice could be the cause of the defective maintenance of Ab titers. Moreover, an aberrant accumulation of extra-follicular (EF) derived immature plasmablasts (PBs) was observed in this tissue potentially hampering the homing or maintenance of the Ag-specific PCs. Interestingly, in WM, mutations of CXCR4 are systematically associated with MYD88 mutations. Thus, the second part of my PhD focused on the study of the MyD88-dependent response in Cxcr4+/1013 mice. We showed that the Cxcr4 gain of function led to an increased cell cycle entry of splenic B cells that was associated with an enhanced PC differentiation. Finally, our findings showed that the desensitization of Cxcr4 is an essential break limiting the EF response as well as PC differentiation and maturation and suggest that an accumulation of mutated PB in the BM is not only due to the gain of function of Cxcr4 but to a more global change in the migratory code of these cells controlled by the exacerbated Cxcr4/Cxcl12 signaling
Verleyen, Stijn. „Fonction, forme et variation : analyse métathéorique de trois modèles du changement phonique au XXe siècle, 1929-1982 /“. Leuven ; Paris ; Dudley : Ma : Peeters, 2008. http://catalogue.bnf.fr/ark:/12148/cb414383627.
Der volle Inhalt der QuelleMorin, Denis. „Le récepteur V2 humain de la vasopressine : perte de fonction et gain de fonction. Du Diabète Insipide Néphrogénique à un récepteur V2 constitutivement actif“. Montpellier 1, 1999. http://www.theses.fr/1999MON1T007.
Der volle Inhalt der QuelleBiajoux, Vincent. „Impact d’un gain de fonction de Cxcr4 sur le développement et la compartimentalisation périphérique des lymphocytes“. Thesis, Paris 11, 2013. http://www.theses.fr/2013PA114825/document.
Der volle Inhalt der QuelleThe WHIM Syndrome (WS) is a rare combined immuno-hematological disorder caused by inherited heterozygous autosomal dominant mutations in CXCR4, which result in most cases in the distal truncation of the receptor’s Carboxyl-terminal tail (C-Tail). Mutants of CXCR4 associated with WS display impaired desensitization and internalization of the receptor upon CXCL12 exposure, leading to enhanced migratory response. Because CXCR4 is expressed on leukocytes, we hypothesized that circulating pan-leukopenia could arise from altered CXCR4-mediated signalling that would skew tissue distribution and differentiation of leukocytes. This assumption was obviously difficult to address in patients. By generating a knock-in mouse strain (Cxcr4+/1013) that harbors a WS-linked gain-of-Cxcr4-function mutation, we establish that the C-tail domain in Cxcr4-mediated signalling is a pivotal regulator of lymphocyte development, peripheral trafficking and humoral immunity. The essential findings of our work, obtained by combining biochemical, bone marrow (BM)-mixed chimeras, in vivo labelling, adoptive co-transfers and functional approaches, are: 1) the C-tail truncating Cxcr41013 mutation caused differential signalling capacities depending on its heterozygous versus homozygous status and inhibited double-negative (DN) 2-to-DN3 and pro-B-to-pre-B developmental transitions during lymphopoiesis. In contrast, it had no effect on NK lymphopoiesis and granulopoiesis; 2) the resulting circulating B and T lymphopenia was due to hematopoietic cell-intrinsic defects and followed a mutated allele dose-dependent pattern; 3) impaired Cxcr41013 desensitization prevented the release of immature BM NK and B cells and mature lymph node (LN) B and T lymphocytes into the blood. Conversely, it forced homing and retention of mature recirculating B and T cells in the BM parenchyma; and 4) despite the absence of primary B-cell follicles in LNs, mutant mice produced efficient humoral responses upon immunization as illustrated by increased antigen-specific germinal center B cells and isotype-switched plasma cells. Collectively, our findings demonstrate that fine-tuning of Cxcr4 signal strength is required for optimal trafficking, egress and fitness of lymphocytes
Bouis, Delphine. „Etude des conséquences d’un gain de fonction de Sting chez la souris : modèle STING V154M/WT“. Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ063.
Der volle Inhalt der QuelleIn humans, point mutations in STING gene, such as V155M, lead to a severe autoinflammatory disease called SAVI (Sting associated vasculopathy with onset in infancy), classified as interferonopathy and characterized by vasculopathy, pulmonary fibrosis and a lupus-like pathology. In order to better understand the pathophysiology of SAVI, we generated a mouse model with the corresponding mutation, using CRISPR/Cas9 technology. These STING V154M/WT mice develop a SCID (severe combined immunodeficiency disease) with decrease of peripheral T, B and NK cells, and expansion of myeloid compartment. This defect seems to be present since the early stages, i.e. pre-proB cells stage in bone marrow and DN2 stage in thymus, and seems intrinsic to hematopoiectic cells. In addition, these mice present a strong hypogammaglobulinemia. Mature T and B cells also present intrinsic defaults. Finally, these mice present an IFN signature but their phenotype is independent of the IFN pathway. These results highlight an important role of STING in lymphoid development
Pronier, Elodie. „Etude de la fonction de TET2 dans l'hématopoïese normale et pathologique“. Paris 7, 2013. http://www.theses.fr/2013PA077035.
Der volle Inhalt der QuelleMyeloid malignancies are clonal disease of the hematopoietic stem cell develop following a skewed of the differentiation toward myeloid lineages associated with increased proliferation. Recently, many studies have demonstrated the involvement epigenetic factors in malignant transformation. Indeed, DNA sequencing of patients with diverse malignancies identified mutations in TET2 (TET methylcytosïne dioxygenase 2) gene. This gene encodes an enzyme that couverts 5-methylcytosines to 5-hydroxyméthylcytosines (5hmC). The biological impact of this new modification of DNA bases and the TET protein function during hematopoiesis is poorly understood. The objectives of my thesis were to determine the function(s) of TET2 in human hematopoiesis and involvement in malignant transformation. My results confirmed in the cells from MPN patients that TET2 mutation induces a decrease in the overall rate of 5hmC. Then we hâve shown that TET2 haploinsufficiency after infection of CD34+ using a specific shRNA induces differentiation skewed toward myeloid lineage. This haploinsufficiency also affects the terminal stages of myeloid three lineages. We also demonstrated that TET2 inhibition induces expression of several inflammatory cytokines such as MIF (Macrophage Migration Inhibitory Factor}. TET2 binds to it promoter regions and influence their transcription through the recruitment of EGR1 and active polymerase II. Finally, haploinsufficiency of TET2 induces a selective advantage of CD34+ cells for reconstitution of the hematopoietic System of highly immunodeficient mice. TET2 is involved in several steps of tumor transformation but these functions factor transcription remain poorly understood
Bozhilov, Yavor. „Analysis of a gain-of-function mutation that produces a new transcriptional unit in the α-globin locus“. Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:c6979237-b318-47a6-ba03-8aab85c33d63.
Der volle Inhalt der QuelleHattori, Tetsuhisa. „A novel gain-of-function KCNJ2 mutation associated with short QT syndrome impairs inward rectification of Kir2.1 currents“. Kyoto University, 2012. http://hdl.handle.net/2433/157461.
Der volle Inhalt der QuelleBillet, Sandrine. „Caractérisation in vitro et in vivo d'un mutant "Gain de Fonction" du récepteur AT1a de l'angiotensine II“. Paris 5, 2006. http://www.theses.fr/2006PA05N15S.
Der volle Inhalt der QuelleAngiotensin II (AngII) is the principal effector of the Renin-Angiotensin-Aldosterone-System (RAAS) that regulates blood pressure (BP) and hydroelectrolytic balance. AngII acts on its target organs via G protein coupled receptors like AT1 receptor. The goal of this work was to characterize the in vitro and in vivo phenotype of a «gain of function» mutant of the AngII AT1A receptor. We selected a mutant bearing a constitutively activating mutation and a deletion which deteriorates receptor desensitizing. The expression of this mutant in mouse leads to moderate hypertension, absence of desensitizing to AngII, modification of the RAAS and deterioration of cardiac function. This new transgenic mice model opens new perspectives for the studying of mechanisms controlling BP and for the direct role of AngII through AT1A receptor on the target organs of the RAAS
Freitas, Christelle. „Impact d’un gain de fonction de CXCR4 sur la différenciation des cellules souches et des progéniteurs hématopoïétiques“. Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS099.
Der volle Inhalt der QuelleThe Warts, Hypogammaglobulinemia, Infections and Myelokathexis Syndrome (WS) is a rare immuno-hematological disorder characterized notably by a pan-leukopenia. It is mostly caused by heterozygous autosomal dominant gain-of-function mutations in CXCR4, which engender a distal truncation in the carboxyl-terminal tail domain and lead to a desensitization-resistant receptor. The in vivo impact of a gain-of-CXCR4 function on lymphocyte development and differentiation remain to be established. Then we recently produced major breakthroughs in the pathophysiology of the WS by generating a mouse strain harbouring a WS-linked heterozygous Cxcr4 mutation. The aim of my PhD was to determine if a HSPC differentiation defect would account for the lymphopenia. We showed that the total number and the clonogenicity of HSC were not altered in the BM of mutant mice. However, HSC carrying the gain-of-function mutation in Cxcr4 have an increased quiescence but a decreased multipotency and self-renewal. These HSC compartment deregulations lead to a in vivo and in vitro decline of multipotent progenitors (MPP) production and lymphoid specification. Furthermore, we reported a decrease in the total number of HSPC in the blood of mutant mice, an anomaly also found in four WS patients carrying a heterozygous CXCR4 mutation. This suggested an abnormal HSPC circulation that was strengthened by an enhanced extramedullary haematopoiesis observed in the spleen of mutant mice. These results suggest that Cxcr4 desensitization regulates HSC quiescence, multipotency and self-renewal and is required for MPP lymphoid specification. In this respect, the absence of such process could account for the lymphopenia in this model and likely in patients
De, Zulueta Pablo. „Caractérisation fonctionnelle de la protéine homéotique teashirt (TSH) : analyse d'un mutant de gain-de-fonction inductible et fonction inductible et identification de trois nouvelles cibles de TSH“. Aix-Marseille 2, 1994. http://www.theses.fr/1994AIX22068.
Der volle Inhalt der QuelleBrasseur, Gaël. „Relations structure-fonction du complexe bc1 chez Saccharomyces cerevisiae : étude de mutants affectés au centre QN de réduction des quinones et d'un mutant d'origine nucléaire“. Aix-Marseille 1, 1995. http://www.theses.fr/1995AIX11010.
Der volle Inhalt der QuelleBehrendt, Anna. „Proteomic and transcriptomic investigation of the mechanisms and consequences of p53 gain of function mutation in laryngeal squamous cell carcinoma“. Thesis, University of Liverpool, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.569205.
Der volle Inhalt der QuelleHumbert, Aline. „La mutation de l'office du juge français : réflexions sur l'influence du droit d'origine externe sur la fonction juridictionnelle“. Université Robert Schuman (Strasbourg) (1971-2008), 2005. http://www.theses.fr/2005STR30019.
Der volle Inhalt der QuelleEvolution of the French internal judicial function has been particularly influenced by the increasing opening up of the internal legal order to international, European community and European human rights laws. Such evolution is mainly analysed through the administrative jurisdiction but doesn't exclude private law or constitutional law judges. The present dissertation focuses on how the legal function is adjusting to its new role of harmonization between internal and external legal systems. As such the first step is to question the judge's capacity to develop the suitable instruments to carry out such responsibility and the second step is to question his capacity to incorporate his new findings. The end result may vary but the role of the judge, from an internal viewpoint, is more valuable and also more complex given its integration to the European judicial network. The traditional institutional framework is therefore affected. It is advisable then to reflect on the judge's legitimacy criteria
Vaglio, Philippe. „Etude de la relation structure-fonction de la protéine kinase CK2 par mutagenèse dirigée des résidus basiques conservés“. Montpellier 1, 1996. http://www.theses.fr/1996MON1T029.
Der volle Inhalt der QuelleVolat, Fanny. „Rôle des aldose réductases dans la physiologie du tissu adipeux blanc : modèles génétiques murins perte et gain de fonction“. Phd thesis, Université Blaise Pascal - Clermont-Ferrand II, 2011. http://tel.archives-ouvertes.fr/tel-00686589.
Der volle Inhalt der QuelleEller, Carla. „Un criblage gain-de-fonction identifie CDKN2C comme facteur d'hôte impliqué dans le cycle viral du virus de l'hépatite B“. Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ103.
Der volle Inhalt der QuelleHepatitis B is caused by the hepatitis B virus (HBV) and is a major cause of progressive liver disease including cirrhosis and hepatocellular carcinoma (HCC), the second leading cause of cancer death worldwide. HBV infects human hepatocytes, and, because of the tiny size of its genome, depends on multiple host functions, contributing to species and tissue tropism. However, fundamental virus-host interactions remain obscure, owing to the lack of robust infectious models for HBV research. An innovative functional genomics screen revealed the role of CDKN2C as proviral host factor promoting HBV replication in a step of the life cycle after the formation of covalently closed circular (ccc) DNA via its function as cell cycle regulator. This provides a better understanding of virus-host interactions and limitations of currently available cell culture systems, and will contribute to the development of physiological infectious model systems and novel therapeutic strategies for viral cure
Tast, Benjamin [Verfasser], Rolf [Akademischer Betreuer] Marschalek, Rolf [Gutachter] Marschalek und Halvard [Gutachter] Bönig. „Einfluss einer CXCR4 gain-of-function Mutation auf die (un)reife Hämatopoese / Benjamin Tast ; Gutachter: Rolf Marschalek, Halvard Bönig ; Betreuer: Rolf Marschalek“. Frankfurt am Main : Universitätsbibliothek Johann Christian Senckenberg, 2019. http://d-nb.info/119237214X/34.
Der volle Inhalt der QuelleGoßmann, Jennifer [Verfasser], und Andreas [Akademischer Betreuer] Neubauer. „Einfluss einer gain-of-function-Mutation im Plcg2-Gen auf eine Helicobacter felis-induzierte gastrale MALT-Lymphom Entwicklung / Jennifer Goßmann. Betreuer: Andreas Neubauer“. Marburg : Philipps-Universität Marburg, 2016. http://d-nb.info/1082347108/34.
Der volle Inhalt der QuelleDeblonde, Jean-Philippe. „Exploitation de la dynamique du geste en IHM : application aux fonctions de transfert pour le pointage et l'extraction d'événements discrets“. Thesis, Lille 1, 2012. http://www.theses.fr/2012LIL10189.
Der volle Inhalt der QuelleThe dynamic of the gesture is not used a lot in the domain of human-computer interaction,while it can help to define some simple heuristics to analyze the intents of users.Its first use is related to transfer functions for isotonic devices. Those functions establisha relationship between the gesture of the user, executed in motor space with the pointingdevice (i.e. a mouse), and the movement of the pointer in the visual space. The transferfunctions used by modern operating systems are still not well known, even if somestudies have shown they have an impact on user’s performance. To characterize thosefunctions, we have developed an electronic device which simulates a real mouse, and thatcan retrieve the transfer functions of any system. We have then exposed the functions ofthe Windows, Linux and Mac systems, and we observed some visible differences betweenthose functions. We have then tried to optimize those functions by reducing their numberof degrees of freedom. By varying those parameters in an exhaustive way, we have thenobserved some significant differences that show there is a family of functions for whichperformances are optimal. Finally, we were interested in the use of the dynamic of thegesture in another context : the generation of discrete events, useful when dealing withcontact-less interfaces, like the Kinect. We have shown that it is possible to distinguishbetween picking and drag’n’drop in a 3D interaction task. The technique is then improvedin the case of small size targets, and its application in a 2D interaction context isevaluated
Plantier, Jean-Luc. „La thrombine dans la physiopathologie vasculaire : une étude structure-fonction“. Université Joseph Fourier (Grenoble), 1994. http://www.theses.fr/1994GRE10179.
Der volle Inhalt der QuelleTadmouri, Abir. „Les déterminants moléculaires et cellulaires de la mutation humaine R482X de la sous-unité Cavb4 impliqués dans l’épilepsie“. Université Joseph Fourier (Grenoble), 2007. http://www.theses.fr/2007GRE10081.
Der volle Inhalt der QuelleHigh voltage-activated (HVA) calcium channels are hetero-multimeric complexes that translate electrical signals into Ca2+ influx, a secondary messenger that mediates essential neuronal processes such as neurotransmitter release and neuronal excitability. HVA calcium channels are composed of four subunits: Cavα1 subunit, the pore forming of the channel and the auxiliary subunits Cavβ, Cavα2δ and Cavγ. The Cavß subunit has focused much of the interest owing to its regulatory functions within the complex. By masking an endoplasmic retention signal on the Cavα1 subunit, Cavß subunit targets the mature calcium channel to the plasma membrane and contributes to the increase in number of functional calcium currents. In humans, pathologic mutations have been identified in CACNAB4 that produce epileptic phenotype. One of these mutations is a premature termination mutation (R482X). Mutations produced minor biophysical effects on calcium channels in spite of their preponderant pathological phenotypes, which tend to indicate that cellular functions other than channel regulation may be responsible for the predominant neurological effects of the R482X mutation. My thesis focuses on the molecular and cellular determinants of the Cavb4 mutant (R482X) inducing the human neurological phenotype. Studies were realized in hippocampal neurons which are particularly implicated in epilepsy. A translocation of endogenous Cavß4, from the cytoplasm to the nucleus is observed during neuronal differentiation and synaptogenesis. This translocation is conditioned by the native structural conformation of Cavß4 subunit; carboxy-terminal deletion inhibits the nuclear localization of the mutant. The 38 amino acids deletion disturbs the structure of Cavß4 by altering the intramolecular interaction between the two conserved domains in Cavß4 subunit. In hippocampal neurons, this structural distortion prevents the nuclear localization of the mutant Cavß4. In order to identify the impact of the nuclear localization of the Cavß4 subunit on transcriptional regulation, a study on gene expression generated by microarray is realized. Profiles of gene expression revealed a differential gene regulation between wild-type and mutant Cavß4. Cavß4 subunit seems to have a repressive action on gene regulation; on the other hand, the lack of nuclear localization of the mutant reverses this repressive impact. Among the specific transcripts differentially expressed, some genes are primordial keys in neuronal activities, thus alterations in the regulation of these genes could be involved in neuronal diseases. Since no NLS consensus sequence has been identified on Cavß4, two-hybrid assay was realized in order to identify partners responsible of the Cavß4 nuclear targeting. A specific protein holding a NLS sequence interacts specifically with Cavß4 subunit, but not with the mutant, and is able to target Cavß4 to the nucleus. The other protein which specifically interacts with the WT Cavß4 sequesters Cavß4 in the cytoplasm. Finally, the lack in nuclear targeting of the R482X mutant due to the structural distortion appears to alter the transcriptional gene regulation which is maybe implicated in the epileptic phenotype of patients holding the mutation
Nguidjoe, Evrard. „Etude de la fonction de la cellule bêta pancréatique dans un modèle de souris présentant une mutation nulle partielle de l'échangeur sodium/calcium“. Doctoral thesis, Universite Libre de Bruxelles, 2011. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209833.
Der volle Inhalt der QuelleDes méthodes biologiques et morphologiques (imagerie du Ca2+, capture de Ca2+, métabolisme du glucose, sécrétion d'insuline et morphométrie par comptage de points) ont été utilisées pour évaluer la fonction de la cellule β in vitro. Les taux de glucose et d'insuline dans le sang ont été mesurés afin de déterminer le métabolisme du glucose et la sensibilité à l’insuline in vivo. Des îlots ont été transplantés sous la capsule rénale pour évaluer leur capacité à corriger le diabète chez les souris rendues diabétiques par l’alloxane.
L'inactivation hétérozygote de Ncx1 chez les souris provoque une augmentation de la sécrétion d’insuline induite par le glucose avec un renforcement important à la fois de la première et de la deuxième phase. Ces résultats s’accompagnent d’une augmentation de la masse et de la prolifération des cellules β. La mutation augmente également le contenu en insuline, l’immunomarquage de la proinsuline, la capture de Ca2+ induite par le glucose et la résistance à l'hypoxie des cellules β. En outre, les îlots de souris Ncx1+/- montrent une capacité à compenser le diabète 2 à 4 fois plus élevé que les îlots de souris Ncx1+/+ lorsque transplantés chez des souris diabétiques.
En conclusion, l’inactivation de l'échangeur Na/Ca conduit à une augmentation de la fonction de la cellule β, de sa prolifération, de sa masse et de sa résistance au stress physiologique, à savoir à divers changements de fonction des cellules β opposés aux principales anomalies rencontrées dans le diabète de type 2 (Type 2 Diabetes Mellitus,T2DM). Ceci nous procure un modèle unique pour la prévention et le traitement du dysfonctionnement des cellules β dans le T2DM et pour la transplantation d'îlots.
Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished
Brilland, Laurent. „Étude et réalisation de réseaux de Bragg inscrits dans une fibre optique monomode pour une fonction d'égalisation du gain des amplificateurs à fibre dopée“. Lille 1, 2000. https://pepite-depot.univ-lille.fr/RESTREINT/Th_Num/2000/50376-2000-504.pdf.
Der volle Inhalt der QuelleUn effort de modélisation nous a conduit à réaliser des fibres à structures d'indice particulières dans lesquelles nous avons inscrit des réseaux à pas longs mieux adaptés à la fonction d'égalisation. Les deux techniques d'inscription (photoinscription et déformation locale) sont analysées. Nous présentons un travail théorique et expérimental sur les caractéristiques spectrales des réseaux à traits inclinés photoinscrits dans une fibre à gaine photosensible. La stabilisation thermique de ces composants par un dispositif passif a été également effectuée. Une courbe de gain d'amplificateur à fibre dopée à l'erbium rendu uniforme par des réseaux à traits inclinés est présentée
Jacquet, Eric. „Relations structure-fonction du domaine d'ef-tu liant les nucleotides guanyliques : mutation de la val20, residu homologue a la position 12 de la p21“. Paris 6, 1988. http://www.theses.fr/1988PA066307.
Der volle Inhalt der QuelleJacquet, Eric. „Relations structure-fonction du domaine d'EF-Tu liant les nucléotides guanyliques mutation de la Val20, résidu homologue à la position 12 de la p21 /“. Grenoble 2 : ANRT, 1988. http://catalogue.bnf.fr/ark:/12148/cb376144130.
Der volle Inhalt der QuelleAguissa, Toure Almass-Houd. „Bases moléculaires de l'anémie de Diamond-Blackfan : étude structure-fonction de la protéine ribosomique RPS19 chez Saccharomyces cerevisiae“. Toulouse 3, 2008. http://thesesups.ups-tlse.fr/427/.
Der volle Inhalt der QuelleDiamond-Blackfan Anaemia (DBA) is a rare congenital erythroblastopenia associated with mono-allelic mutations in several ribosomal protein genes. This linkage suggests a causal relationship between alteration of ribosome biogenesis or functions and this pathology. ?The RPS19 gene is the most frequently mutated (25% of patients). To understand the impact of the mutations, especially missense mutations, we undertook a structure-function study of RPS19 homolog in yeast Saccharomyces cerevisiae and we conducted a collaborative work to determine the crystal structure of archeae Pyrococcus abyssi RPS19. Our results distinguish two types of mutations: some affect residues buried in the structure and alter the protein folding and stability, while others change amino acids at the protein surface and prevent incorporation of RPS19 into 40S pre-ribosomal particles. In addition, we determined the nuclear localization sequence and the molecular determinants of RPS19 transport to the nucleus. Mutations linked to DBA do not interfere with the nuclear localization of the protein. Thus, missense mutations in RPS19 primarily affect the ability of the protein to be incorporated into pre-ribosomes, which alters ribosome biogenesis. This could on the one hand activate a stress response and on the other hand lead to ribosome shortage, two events that could be fatal to some physiological processes like erythropoiesis. A similar mechanism can be proposed for any ribosomal protein mutated to the DBA
Mazza, Catherine. „17-hydroxystéroïde déshydrogénase humaine de type I : analyse des relations structure-fonction par mutagenèse dirigée et cristallographie des rayons X“. Université Joseph Fourier (Grenoble ; 1971-2015), 1997. http://www.theses.fr/1997GRE10214.
Der volle Inhalt der QuellePyun, Hae-Ok. „Les carrières nomades [motiles] constituent-elles une réponse face à un environnement en mutation? : Etude de cas sur les administrateurs territoriaux“. Paris 2, 2010. http://www.theses.fr/2010PA020095.
Der volle Inhalt der QuelleBrillet, Thomas. „Relations structure-fonction de l'alpha-hémoglobine et de sa protéine chaperon l'AHSP : octamères d'hémoglobine recombinante : application à la mise au point d'un transporteur d'oxygène artificiel“. Paris 7, 2010. http://www.theses.fr/2010PA077097.
Der volle Inhalt der QuelleThis work concerns the study of two candidate molecules of hemoglobin (Hb) in the development of an artificial oxygen carriers and the study of structure-function relationships of α-Hb and its chaperone AHSP in the context of a mutant AHSP described in a patient with thalassemia syndromes. The first part of the work concerns the mutant α-HbH⁵⁸L, a key residue of the heme pocket in order to reduce auto-oxidation in Hb. This mutant has the same spectral characteristics regardless of the external ligand added, unlike the native protein. This mutant appears to have a hexacoordinated heme with a high affinity endogenous ligand. The second part concerns the study of recombinant Hb octamers Hb, obtained by intermolecular disulfide bond of ß-Hb (ß octamer) or α-Hb (α octamer). These octamers have functional properties similar to HbA, but with a decreased interaction with haptoglobin (Hp). Hp and a octamer form within a few hours a large complex while the ß octamer reacts much more slowly with Hp, reflecting its greater stability. The third part concerns the characterization of the complex AHSP/α-Hb. Both association and dissociation rates of the α-Hb with its chaperone were determined. For the mutant AHSPV⁵⁶G, the dissociation rate of the complex AHSP/α-Hb is 4 times reduced. The AHSPV⁵⁶G appears to be partially folded at 37 ° C with a progressive thermal unfolding curve. However the complex AHSPV⁵⁶G/α-Hb has a thermal stability close to normal. Within the complex AHSPV⁵⁶G/α-Hb, the α-Hb displays a normal function
KEMTCHOU, JASMINE. „Contribution a l'etude de la qualite et de la fiabilite des amplificateurs optiques a fibre dopee erbum : modelisation du gain et du bruit en fonction des contraintes climatiques“. Paris 11, 1997. http://www.theses.fr/1997PA112106.
Der volle Inhalt der QuelleVirot, Sophie. „Les petites protéines de stress et leur rôle dans la mort cellulaire : étude de leur fonction chaperon à travers l'exemple de la mutation R120G del'[alpha]B-cristalline“. Lyon 1, 2004. http://www.theses.fr/2004LYO10095.
Der volle Inhalt der QuelleScekic-Zahirovic, Jelena. „Troncation conditionnelle de la protéine FUS chez la souris : un nouveau modèle animal du continuum sclérose latérale amyotrophique/démence fronto-temporale“. Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ002/document.
Der volle Inhalt der QuelleAmyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTLD) are now considered as a unique clinicopathological spectrum referred to as ALS/FTLD. Cytoplasmic aggregation of the physiologically nuclear FUS protein is a hallmark feature of a subset of ALS/FTLD. It remains unknonwn whether the critical pathogenic event relies on a loss of FUS normal nuclear functions, a toxic gain of function of FUS in the cytoplasm, or a combination of both.To answer this question we have generated a conditional mouse model expressing truncated FUS without nuclear localization signal - FusΔNLS. Our data showed that complete cytoplasmic mislocalization of truncated FUS protein within spinal motor neurons is a major determinant of motor neuron degeneration via toxic gain of function. A partial mislocalization of truncated FUS protein was sufficient to trigger key features of ALS and of FTLD.These studies allowed the elucidation of mechanisms underlying FUS role in ALS/FTLD, and will hopefully lead to development of therapies for these devastating diseases
Mouz, Nicolas. „Mécanismes de résistance aux [bêta]-lactamines : études des relations structure-fonction de la Penicillin-Binding Protein 2x de Streptococcus pneumoniae“. Université Joseph Fourier (Grenoble), 1999. http://www.theses.fr/1999GRE10102.
Der volle Inhalt der QuelleRenault, Anne-Laure. „Identification de facteurs génétiques modifiant le risque de cancer chez les porteuses d'une mutation constitutionnelle d'ATM & profil tumoral des tumeurs du sein associées à une perte de fonction d'ATM“. Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS389/document.
Der volle Inhalt der QuelleInherited biallelic mutations in the ATM gene cause Ataxia Telangiectasia (A-T), a multisystemic disorder characterized by neurological, cutaneous and immunological abnormalities. The disease is associated with an elevated risk of malignancies, particularly of lymphoma or leukemia, and a high radiosensitivity. Epidemiological studies have shown that female heterozygote carriers (HetAT) younger than 50 years are at increased risk of breast cancer, as compared to women from the general population (RR 4,94, 95%CI 1,90 - 12,09). Despite the rarity of A-T disease, 0.5 to 1% of the population is estimated to be HetAT. Epidemiological studies have confirmed that some specific truncating or missense variants in ATM are associated with increased breast cancer risk but this risk is not yet well estimated. The first part of my thesis project has consisted in characterizing inherited genetic factors modifying cancer risk in women participating in the prospective cohort CoF-AT (“cohorte de femmes apparentées à un enfant atteint d’A-T). In the second part of my work, I described the morphological and molecular features of ATM breast tumours with the aim to identify biomarkers allowing to distinguished ATM-associated tumours from sporadic tumours.Assessment of the contribution of inherited factors such as SNPs of telomere length on the risk of cancer was performed on 284 HetAT individuals and 174 non-HetAT individuals belonging to 103 A-T families. We showed that HetAT individuals have longer telomeres than their non-HetAT counterparts (p=0.0008). However, we found that telomere length was not associated with cancer risk in our study population. The SNP rs9257445 (ZNF311), which is associated with telomere length in HetAT participants, was not associated with cancer risk. Conversely, SNPs rs6060627 (BCL2L1) and rs2380205 (ANKRD16) modified cancer risk in HetAT and non-HetAT women.Pathology review of 41 ATM-associated breast tumours revealed that these tumours mostly belonged to luminal B molecular subtype. The molecular characterization of 23 ATM-associated tumours did not revealed the BRCAness profile associated with Large-Scale State Transitions. However, we found that ATM tumours were mostly tetraploïd and observed loss of heterozygosity at 11q22-23 in the majority of the tumours and loss of ATM wild type allele. Moreover, copy number losses at loci 13q14.11-q14.3, 21p11.2-p11.1 and 22q11.23 appeared to be specific of ATM tumours.Altogether, this project allowed to better characterize the genetic background of the CoF-AT participants and to highlight biomarkers of ATM breast tumours
Albiges-Sauvin, Laurence. „Caractérisation des Carcinomes Papillaires du Rein“. Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T070.
Der volle Inhalt der QuellePapillary renal cell carcinomas (pRCC) are the second most common form of Renal Carcinomas and belongs to the non clear cell carcinomas family. This tumour type is an heterogeneous group of tumours usually subdivided in type I and type II according to pathological features. The prognosis of pRCC in the metastatic setting is worse to clear cell carcinoma’s prognosis. Biological characteristics of pRCC are poorly known and did not allow the development of specific targeted therapies.This work first presents a synthesis of published data regarding biology, pathology, therapeutics and prognosis of pRCC. This review has been published. (Albiges et al. The Oncologist 2012)Second part is dedicated to the analysis of MET proto-oncogene across pRCC. The main focus is to assess MET activation drivers. This analysis (i) characterises MET gene DNA copy number alterations (CGH array for type II pRCC and CGMA approach for Type I pRCC) and their correlation with gene expression profiling; (ii) assess activating mutations within the tyrosine kinase of MET gene in the type I pRCC; and (iii) investigate expression level of ligand and co-activators of MET receptor. This analysis is under publication. (Albiges et al. Clinical Cancer Research)Third and last part of this work aims at identifing new biological pathway specific to pRCC using clustering of gene expression profiling and DNA abnormalities assessed by CGHarray inthe type II pRCC subtypes with matching gene expression data
Aghion, Joël. „Le virus polyome et les cellules de carcinome embryonnaire murin : expression et réplication virales en fonction de l'état de différenciation“. Paris 6, 1986. http://www.theses.fr/1986PA066003.
Der volle Inhalt der QuelleHuet, Tiphaine. „Exploitation de la relation structure-fonction du récepteur nucléaire de la vitamine D pour l’élucidation des mécanismes de la signalisation de la vitamine D“. Strasbourg, 2010. https://publication-theses.unistra.fr/public/theses_doctorat/2010/HUET_Tiphaine_2010.pdf.
Der volle Inhalt der QuelleGenetic expression is regulated by transcriptional factors. Among them, the Vitamin D receptor (VDR) belongs to the superfamily of nuclear receptors which adopt their active conformation upon ligand binding. The active form of Vitamin D, Calcitriol is the natural ligand of VDR and plays important roles in several biological functions such as calcium and phosphate homeostasis, inflammation, cell differentiation and proliferation and apoptosis. However, its intrinsic genomic actions are accompanied by hypercalemic nongenomic effects which limit the use of Calcitriol in therapeutic treatments. To further dissociate the antitumor actions of Calcitriol from its hypercalcemic effects, the challenge is to decipher the mechanisms involved in the non-genomic pathway from those involved in the genomic one. Previously, we identified the Leu337 of zebrafish VDR as a key residue in the adaptability of the ligand binding domain. Then, a classical mutagenesis study stressed a surprising finding : the VDR Leu337His abolishes the genomic activity of VDR in presence of Calcitriol but not in presence of the synthetic double-chained Gemini ligand. The results of my thesis confirm that as for the wild-type human and zebrafish VDRs, both zebrafish VDR Leu337His and human VDR Leu309His behave similarly in presence of Calcitriol and Gemini in terms of ligand binding and transactivation. The structural study conducted in parallel emphasizes a crucial interaction for the stabilization of Calcitriol. In sharp contrast, the mutation Leu337His has a neutral incidence on the stabilization of Gemini and the two Gemini derivatives studied. Moreover, the structural findings reveal that double-chained ligands are less sensitive to structural modifications targeting the network of ligand/residues interactions. This study relates the structural and molecular basis for the design of an original animal model (knock-in-mice expressing the corresponding mutation Leu337His) which will allows us to switch on/off the nuclear VDR following the presence of Calcitriol or Gemini, and to gain insight into the non-genomic pathway induced by Calcitriol. My work enrolls a multi-disciplinary approach, from atomic structure to the organism and the integration of the in vivo data will provide us with a better understanding of the Calcitriol signalization and with the development of highly specific new treatments
Israel, Nicole [Verfasser], Katharina [Akademischer Betreuer] Riedel, Ulrike [Akademischer Betreuer] Seifert, Katharina [Gutachter] Riedel, Ulrike [Gutachter] Seifert und Luca [Gutachter] Simeoni. „The role of the immunoproteasome during Toxoplasma gondii infection and the characterization of SHP2D61Y gain-of-function mutation in T cells / Nicole Israel ; Gutachter: Katharina Riedel, Ulrike Seifert, Luca Simeoni ; Katharina Riedel, Ulrike Seifert“. Greifswald : Universität Greifswald, 2020. http://d-nb.info/1206688408/34.
Der volle Inhalt der QuelleGuénard, Sophie. „Fonction et dysfonction des systèmes d'efflux actif chez les souches cliniques de pseudomonas aeruginosa“. Thesis, Besançon, 2013. http://www.theses.fr/2013BESA3003/document.
Der volle Inhalt der QuellePseudomonas aeruginosa is a nosocomial pathogen naturally resistant to many antibiotics thanks to numerous resistantmechanisms. Among them, overproduction of the MexXY/OprM efflux System leads to decrease significantly thesusceptibility of P. aeruginosa to aminoglycosides, fluoroquinolones and some p-lactams. Characterization of geneticmechanisms leading to overproduction of this pump from a collection of 57 non-redundant clinical isolates enable toidentified three types of mutations affecting either the gene mexZ whose product represses mexXY operon (agrZmutants, «=77. 2%), or genes parRS encoding a two component System (agrW2 mutants, w=8.8%) or other targetswhose inactivation disturbs protein synthesis and results in overexpression of the gene PA547I, whose product ArmZ isan anti-repressor of MexZ protein (agrWl mutants, n= 14%). If some populations of A aeruginosa are becoming moreresistant to aminoglycosides by overproducing MexXY/OprM system, others develop an hypersensitivity to P-lactamsas a resuit of mutations inactivating MexAB-OprM efflux system (MexAB-). The analysis of 275 strains isolated from36 CF patients allowed us to identify MexAB- strains hypersensitive to ticarcillin (37%) and non-MexABhypersensitive strains due to an overproduction of the p-lactamase AmpC (16%). In fine, 53% of the isolates appeareddeficient in MexAB-OprM. The study of various virulence factors indicated that the loss of function of MexAB-OprMin P. aeruginosa was not associated with virulence of the strains. To conclude, our work highlight on the ability ofP. aeruginosa to modulate the activity of its efflux pumps in order to adapt to various clinical environments
Reilly, Madeline Louise. „Identification and characterisation of loss of function mutations in KIF14 leading to syndromic renal hypodysplasia“. Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC266.
Der volle Inhalt der QuelleMutations in KIF14 were previously shown to lead to either isolated microcephaly or to a developmental and lethal syndromic form associating severe microcephaly with renal hypodysplasia (RHD). The latter phenotype was considered reminiscent of a ciliopathy, relating to defects of the primary cilium, a signalling organelle present on the surface of many quiescent cells. KIF14 encodes a mitotic kinesin which plays a key role at the midbody during cytokinesis, and was not previously shown to be involved in cilia-related functions. Here, we have analysed four families with foetuses presenting with the syndromic form and harbouring variations in KIF14. Our functional analyses show that the identified variations severely impact the activity of KIF14 and likely correspond to loss-of-function (LOF) mutations. 0ur analysis on human foetal kidney tissues revealed the accumulation of KIF14-positive midbody remnants in the lumen of ureteric bud tips, highlighting similarities between mitotic events during early brain and kidney development. Subsequently, analysis of a kif14 mutant zebrafish line showed a conserved role for this mitotic kinesin. Interestingly, additional ciliopathy-associated phenotypes were also present in these mutant embryos, supporting a potential novel role for kif14 at cilia. However, our in vitro and in vivo analyses ultimately indicated that KIF14 does not have a direct role in ciliogenesis and that kif14 LOF in zebrafish phenocopies ciliopathies through an accumulation of mitotic, non-ciliated cells in ciliated tissues. Altogether, our results demonstrate that KIF14 mutations result in a severe syndrome associating microcephaly and RHD through a conserved function in abscission during kidney and brain development
Chevallet, Mireille. „Étude du rôle structural et fonctionnel de la sous-unité NUO I de la NADH:ubiquinone oxydoréductase Rhodobacter capsulatus“. Université Joseph Fourier (Grenoble ; 1971-2015), 1997. http://www.theses.fr/1997GRE10181.
Der volle Inhalt der QuelleGil, Marie-Ève. „Analyse d'équations intégro-différentielles et d'EDP non locales issues de la modélisation de dynamiques adaptatives“. Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0346.
Der volle Inhalt der QuelleThis manuscript is devoted to the mathematical analysis of integro-differential models from population genetics. Both models are reaction-dispersion equations of the form ∂tp(t,m) = UD[p](t,m)+ f[p](t,m). They describe the dynamics of fitness distribution in an asexual population under the effect of mutation and selection. These two processes are represented by the nonlocal terms UD[p](t,m) and by f[p](t,m) respectively. The difference between the models rests on the mutation term. Indeed, in the first model, the mutation effects on fitness do not depend on the fitness of the parent. Thus, the mutation term is a standard convolution product: D[p](t,m) =RR J(m−y)p(t,y)dy −p(t,m). When a mutation occurs, the function J(m − y) represents the density of probability for an individual with fitness y to have an offspring with fitness m. The mutation rate is given by the constant U. In the second model, the mutation effects on fitness depend on the fitness of the parent. In this case, an individual with fitness y has an offspring with fitness m with a probability density Jy(m−y). This type of dependence naturally arises when the existence of an optimal fitness (or a phenotypic optimum) is assumed. For both models, we first establish existence and uniqueness results as well as decay properties of the solution. The decay property allows us to define the cumulant generating function (CGF). The CGF obeys a nonlocal transport equation. In the first model, we compute the analytical solution of this transport equation and thus, we obtain a complete description of the distribution p(t,m) through its moments. Then, we study the stationary states for both models, and establish sufficient conditions for the existence and non-existence of a concentration phenomenon corresponding to an accumulation of individuals with best possible phenotype. The results are compared to the results of stochastic individual based models which represent the same kind of evolutionary dynamics
Zuniga, Dania. „Structural and functional studies of a human potassium channel, Kir2.1. Mechanism and consequences of mutations“. Electronic Thesis or Diss., Sorbonne université, 2022. http://www.theses.fr/2022SORUS336.
Der volle Inhalt der QuelleThe ability of a cell to facilitate the selective and rapid movement of ions and small molecules across the plasma membrane is one of the most fundamental biological processes. Inward rectifier potassium (Kir) channels are integral membrane proteins that provide K+-selective pathways across the otherwise impermeable cell membrane along the electrochemical gradients. Kir channels support the flow of K+ ions into and out of the cell and regulate various functions in the human body, including heart rate, vascular tone, insulin secretion, and salt and fluid balance. The physiological significance of Kir channels is highlighted by the fact that genetically-inherited defects in these genes result in human diseases (channelopathies). We are particularly interested in Andersen’s syndrome, where mutations in the KCNJ2 gene coding for Kir2.1 protein are directly involved. Andersen’s syndrome (AS) is a rare disease characterized by cardiac arrhythmias, dysmorphic features, and periodic paralysis. The available treatment for AS patients is empirical rather than rational due to the lack of knowledge of this Kir2.1 channel. This thesis aimed to identify the differences between the wild-type Kir2.1 channel and two mutant AS-causing channels to find links between the structure and the function of human Kir2.1 using a combination of biochemical, structural, and functional approaches. In this study, we recombinantly expressed the human Kir2.1 channel in yeast and purified it in detergent. We characterized the interaction between Kir2.1 and the essential activator PIP2, solved the first human Kir channel structure by cryo-EM, and explored reconstitution in detergent-free systems like amphipols and nanodiscs. The findings of this study will provide a structural and functional base to understand better the mechanisms involved in Kir channels and the effects of their mutations. This manuscript is divided into three parts. The first part introduces Kir channels and state-of-the-art. The second part focuses on the characterization of the human potassium channel Kir2.1, the determination of its structure by cryo-EM, and the impact of mutations on its structure and function. The third part presents two mutations in the bacterial homolog KirBac3.1, which shares structural features with Kir2.1, to provide insight into the gating mechanism of Kir channels
Vitellius, Géraldine. „Implication du récepteur des glucocorticoïdes en physiopathologie humaine“. Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS256.
Der volle Inhalt der QuelleGlucocorticoids (GC) regulate many essential biological functions by activating the glucocorticoid receptor (GR). GR loss-of function mutations are responsible for GC resistance syndrome, often associated with high blood pressure, hirsutism, bilateral adrenal hyperplasia (BAH) and obesity. Herein, functional characterization of 13 GR variants is presented (expression and binding studies, transactivation assays, subcellular localization) 6 variants were discovered with next-generating sequencing and had no functional impact on GR signaling while 7 GR loss-of-function mutations were mainly discovered during the National Clinical Hospital Research Program, Muta-GR. This PHRC discloses a 5% prevalence of GR loss-of-function mutations in a cohort of 100 patients with BAH, biological hypercortisolism and/or hypertension without Cushing signs. A GR haploinsuffisiency was demonstrated by a reduced dexamethasone-induced FKBP5 expression in skin fibroblasts of some patients harbouring GR loss-of-function mutations. These patients often presented with hypercorticism, hypokalemia, low renin and aldosterone levels, consistent with a pseudohypermineralocorticism. We showed that HSD11B2 encoding the 11β-HSD2 enzyme inactivating GC, is a direct GR target gene by transient transfection of reporter gene, RT-qPCR, LC/MSMS and ChIP. We failed to introduce GR loss-of-function mutations in human preadipocytes and adrenocortical cells by Crispr/Cas 9 technology. This work should facilitate selection of patients in whom GR mutation may be search, enabling an appropriate follow-up
Chollat-Namy, Marie. „Effet de l’inactivation du gène suppresseur de tumeur p53 et de sa réactivation pharmacologique sur la réponse cytotoxique anti-tumorale The Pharmalogical Reactivation of p53 Function Improves Breast Tumor Cell Lysis by Granzyme B and NK Cells Through Induction of Autophagy Mutant P53 Gain of Function Stimulates PD-L1 Expression“. Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL032.
Der volle Inhalt der QuelleImmune system plays an important role in the control and destruction of cancer cells. The major effectors of antitumor immune response are Natural Killer (NK) cells and the cytotoxic T lymphocytes, which recognize et destroy tumor cells by exocytosis of perforin and granzymes contained in cytotoxic granules. It has been previously shown in the laboratory that the tumor suppressor p53 plays an important role in this apoptotic pathway. However more than 50% of human tumors have p53 inactivating mutations which favor tumor development. Consequently, frequent p53 inactivation in human tumor could enable them to escape from destruction by cytotoxic immune cells. In this context, my thesis work has shown that the pharmacological reactivation of wild type p53 function in cancer cells expressing a mutated p53 increased their susceptibility to NK cell-mediated apoptosis cells through the induction of an autophagic process. Moreover, I tried to determine the link between p53 mutations and the expression of the immune checkpoint ligand PD-L1 which prevent efficient activation of cytotoxic cells and promote immune cells exhaustion. My work suggests that the expression of p53 mutants promotes an the expression of PD-L1 at the cancer cell surface. The study of the underlying mechanisms is still in progress