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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
51

Induced pluripotent stem cells from patients with hypoplastic left heart syndrome (HLHS) as a model to study functional contribution of endothelial-mesenchymal transition (EndMT) in HLHS

Liu, Xiaopeng 28 November 2016 (has links)
No description available.
52

Mitochondrial Gene Expression in Human Mononuclear Cells

Ruchala, Monika 01 January 2014 (has links)
MITOCHONDRIAL GENE EXPRESSION IN HUMAN MONONUCLEAR CELLS By Monika D. Ruchała, M.S. A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. Virginia Commonwealth University, 2014. Director: Dr. James P. Bennett Jr, M.D., Ph.D., Bemiss Professor Departments of Neurology, Psychiatry and Physiology and Biophysics Adult neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), have been intensively studied in recent years in pursuit of mechanisms responsible for origin and progression. One emerging theme is mitochondrial energetic deficiency as a mechanism of neuronal death. Recent descriptions of protocols to generate induced pluripotent stems cells (iPSCs) from living patients offer the potential to create unique disease models. This model can potentially lead to crucial advances in developing treatment options for a wide variety of neurodegenerative diseases. In this thesis, we attempt to induce iPSCs from mononuclear cells (MNC) in peripheral blood acquired from patients with ALS and healthy control (CTL) subjects, and analyze their mitochondrial genomes. The reprogramming of MNC to yield iPSC was done by nucleofection of an episomal plasmid pEB­ C5, expressing OriP sequences of the Epstein­Barr and five reprogramming transgenes Oct4, Sox2, Klf4, c­Myc and Lin28. We investigated the expression of mitochondrial DNA genes, ND2, ND4, COXIII and 12s rRNA in the ALS and CTL MNC before and after their culturing. The results implicate deregulated mitochondrial bioenergetics as a characteristic of ALS. Future work will establish whether these abnormalities in mitochondrial bioenergetics persist in iPSC’s and iPSC-derived neurons from ALS subject
53

Genome Studies of Gene Expression and Alternative Splicing During iPSC Skeletal Muscle Induction and Differentiation

Wu, Yibo 31 May 2019 (has links)
Facioscapulohumeral muscular dystrophy(FSHD) is a disorder characterized by muscle weakness and wasting (atrophy). This disease is typically inherited as autosomal dominant and has a complex genetic and epigenetic etiology. Our collaborator had differentiated healthy human pluripotent stem cells(iPSC) into skeletal muscles and exploited ISO-Seq to explore cell gene expression and transcript alternative splicing usage profile during 8 differentiation stages. Later, stage specific gene differential expression, transcript alternative splicing, gene ontology and novel gene/transcript were analysed to characterize the feature of each stage during the differentiation. In terms of expressed genes with more than or equal to 5 transcripts, each stage had shown their own stage specific features. About transcripts, iPS, S1, ADM.D0, ADM.D4 have about 30% to 40% more total transcripts than the rest 4 stages. 4 kinds of alternative splicing events are generally distributed and S2 stage has the least alternative splicing events potentially due to technical reasons. As for gene differential expressions, ADM.D4 has considerable amount of differential expressed genes with 5 other stages and it has minor difference with ISM.D4 and S3 stages(they are all myotubes cells). The gene ontology analysis is performed according to the results of previous step, stage specific GO terms are revealed.
54

Genome Studies of Gene Expression and Alternative Splicing During iPSC Skeletal Muscle Induction and Differentiation

Wu, Yibo 31 May 2019 (has links)
Facioscapulohumeral muscular dystrophy(FSHD) is a disorder characterized by muscle weakness and wasting (atrophy). This disease is typically inherited as autosomal dominant and has a complex genetic and epigenetic etiology. Our collaborator had differentiated healthy human pluripotent stem cells(iPSC) into skeletal muscles and exploited ISO-Seq to explore cell gene expression and transcript alternative splicing usage profile during 8 differentiation stages. Later, stage specific gene differential expression, transcript alternative splicing, gene ontology and novel gene/transcript were analysed to characterize the feature of each stage during the differentiation. In terms of expressed genes with more than or equal to 5 transcripts, each stage had shown their own stage specific features. About transcripts, iPS, S1, ADM.D0, ADM.D4 have about 30% to 40% more total transcripts than the rest 4 stages. 4 kinds of alternative splicing events are generally distributed and S2 stage has the least alternative splicing events potentially due to technical reasons. As for gene differential expressions, ADM.D4 has considerable amount of differential expressed genes with 5 other stages and it has minor difference with ISM.D4 and S3 stages(they are all myotubes cells). The gene ontology analysis is performed according to the results of previous step, stage specific GO terms are revealed.
55

Induced pluripotent stem cell modeling of malaria

Nah, Shirley 22 January 2016 (has links)
Malaria is one of the oldest parasitic diseases known to man, and the disease has played a role in shaping civilizations and the success of human populations over many centuries. While the malaria is well studied, it still remains a worldwide killer--claiming about 600,000 lives annually with children under the age of five representing a disproportionate population of those lethally infected. Malaria is caused by the protozoan parasite Plasmodium, which is introduced to the human body through the bite of a female Anopheles mosquito. The most lethal form of the disease is carried by the parasite Plasmodium falciparum, while the most widespread form of malaria is caused by Plasmodium vivax, the latter of which has a specific mode of entry and life cycle that makes it difficult to eradicate. The entry of P. vivax into human reticulocytes is based on the presence of the Duffy antigen chemokine receptor (DARC), which is uniquely absent in two-thirds of the Black population and populations of immediate African descent making it rare in the African region while endemic in Western and Asian countries. Inability to culture the parasite P. vivax in vitro and exhaustible tissue samples makes an accurate model of P. vivax malaria difficult to maintain ex vivo. The current study focuses on overcoming those limitations by modeling the mode of entry of P. vivax into patient-specific, induced pluripotent stem cell (iPSC)-derived erythrocyte-lineage cells by showing firstly that DARC is a measurable marker of susceptibility in vitro via FACS analysis, and that secondly, P. vivax cell culture limitations can be bypassed by creating a lentivirus designed to specifically infect DARC-expressing cells. To demonstrate the potency of this system, we show that a virus expressing the conserved region of the Duffy binding ligand, Duffy binding protein II (DBPII), can selectively infect peripheral blood mononuclear cells (PBMCs) that express DARC. Moreover, our current study focuses on the development of an iPSC-based disease model using patient samples derived from DARC expressing patients (DARC+) and DARC negative Sickle Cell Disease (SCD) patients (DARC-). We show that DARC+ iPSC-derived erythroid lineage cells express a transient population of DARC-expressing cells via FACS analysis, and we explore different protocols to stabilize this unique population. We hypothesize that DARC is a stage-specific marker for erythrocyte maturation, and we believe that any subset of cells expressing DARC consists of more mature erythrocyte-lineage cells. This study then, provides a novel platform by which to study malaria infection in a patient-specific manner while bypassing the limitations of culturing P. vivax in an in vitro culture system, as well as introducing a new way to measure erythrocyte maturation. Successful establishment of such a disease model has great implications for in-depth drug screenings for novel therapeutics that target the blood stage of the parasitic disease that were previously difficult to validate due to the limitations of currently existing models.
56

Modélisation de la leucémie myelomonocytaire chronique par reprogrammation de cellules de patients. / Modeling chronic myelomonocytic leukemia by reprogramming patients cells

Beke, Allan 29 November 2017 (has links)
La leucémie myélomonocytaire chronique (LMMC) est une hémopathie myéloïde rare attribuée à l’accumulation d’évènements génétiques et épigénétiques dans une cellule souche ou progénitrice hématopoïétique. Les altérations génétiques somatiques récurrentes qui caractérisent cette maladie ont été identifiées: elles associent des altérations cytogénétiques non spécifiques chez 30% des patients et des mutations des gènes de la régulation épigénétique, de l’épissage, de la signalisation et de la transcription. Si certaines mutations influencent le phénotype (les mutations de RUNX1 génèrent une thrombopénie, celles de la signalisation une maladie proliférative, celles de KIT une mastocytose), elles ne sauraient résumer à elles seules l’expression phénotypique de la maladie. D’ailleurs, les médicaments hypométhylants restaurent une hématopoïèse équilibrée en modifiant le contexte épigénétique des cellules malades sans les éliminer. Il n’existe pas de lignée cellulaire de LMMC et les modèles murins n’en récapitulent que très partiellement les caractéristiques. L’objectif de mon travail de thèse a été de générer des cellules modélisant la maladie. J’ai transformé les cellules CD34+ de 2 patients en clones de cellules souches induites reprogrammées. Les clones obtenus à partir de l’un des patients ont été écartés du fait d’altérations génétiques supplémentaires acquises lors de la reprogrammation. Nous avons focalisé nos travaux sur 5 clones établis à partir des cellules CD34+ de l’autre patient et de 5 clones établis à partir de cellules CD34+ de deux sujets sains. Nous avons capturé 2 étapes de l’évolution moléculaire du clone, sans puis avec mutation KRASV12G. La différenciation hématopoïétique de ces clones en milieu semi-solide ou liquide récapitule les principales caractéristiques phénotypiques de la maladie. Par édition de gènes, nous avons ajouté dans certains clones la mutation SRSF2P95H observée dans les cellules de 50% des patients atteints de LMMC mais absente des cellules de la patiente étudiée. Nous montrons que l’hétérogénéité fonctionnelle et épigénétique des clones obtenus dépasse la seule hétérogénéité génétique et que la decitabine, un agent hypométhylant, a un effet cytotoxique faible mais améliorer l’équilibre de la production des cellules hématopoïétiques matures par des cellules génétiquement altérées. / Chronic myelomonocytic leukemia (CMML) is a rare hematological malignancy that has been related to the accumulation of genetic and epigenetic alterations in a hematopoietic stem or progenitor cell. Somatic recurrent mutations of coding DNA sequences have been in CMML cells, combining non-specific cytogenetic aberrations in 30% of the patients and mutations in epigenetic regulator, signal transduction, spliceosome and transcription factor genes. While some of these mutations directly affect disease phenotype (mutations in RUNX1 and thrombocytopeny, mutations in signaling pathways and proliferative disease, mutations in KIT and mastocytosis), they do not sum up the complex disease phenotype of this pathology on their own. Accordingly, hypomethylating agents restore a balanced hematopoiesis without eliminating clonal cells. There is no CMML cell line and murine models only partially recapitulate the disease. The objective of my thesis work was to reprogram hematopoietic stem/progenitor cells in order to model the disease heterogeneous expression. The clones established from one patient cells were discarded as their genetic background had been altered by reprogramming and cell culture. We analyzed in more details the behavior of 5 induced pluripotent stem cell lines established from a second patient and 5 other clones established from 2 healthy donor cells. We had captured 2 distinct genetic backgrounds of the patient clone, without or with KRASG12D mutation. Hematopoietic differentiation of these clones in semi-solid and liquid medium recapitulated the main characteristics of disease phenotype. With a gene editing tool, we introduced in some clones the SRSF2P95H mutation, observed in 50% of patient with CMML but missing in the studied patient. We noticed that functional and epigenetic heterogeneity of the clones exceeded their genetic heterogeneity and that the demethylating agent decitabine had limited cytotoxic effect but restored a more balanced production of hematopoietic cells by genetically abnormal cells.
57

Hémodynamique Artérielle Périphérique :<br />Evaluation diagnostique et fonctionnelle à l'effort dans deux modèles d'artériopathie des membres inférieurs

Le Faucheur, Alexis 21 December 2007 (has links) (PDF)
Les travaux de recherche réalisés ont porté sur l'exploration de la fonction hémodynamique artérielle des membres inférieurs (MI) à l'effort dans deux modèles d'artériopathie. Nos axes de recherche étaient doubles. Notre premier axe de travail s'est inscrit dans une approche diagnostique et a porté sur l'étude de la réponse physiologique et physiopathologique des pressions artérielles systoliques de chevilles à la suite d'un effort maximal, chez des sujets sportifs sains et chez des sujets atteints d'une Endofibrose Artérielle Induite par l'Exercice (EAIE). Le deuxième axe de travail concernait l'évaluation de la capacité de marche de patients atteints d'une Artériopathie Athéroscléreuse Oblitérante des MI (AOMI) en utilisant la technique de Positionnement Global Satellitaire (GPS). Suite aux travaux menés dans le cadre de notre premier axe de travail, nous avons montré que l'âge influençait la réponse physiologique de l'Index de Pression Systolique de Cheville post-effort, ce qui laisse penser que les limites diagnostiques utilisées dans la détection de l'EAIE doivent être très certainement reconsidérées chez des sportifs plus âgés. Par ailleurs, nous avons mis en évidence que des mesures simultanées de pressions artérielles systoliques en récupération offraient, comparativement à des mesures consécutives, une performance diagnostique supérieure dans la détection de l'EAIE. Dans le cadre de notre deuxième axe de travail, nous avons pu valider l'utilisation de la technique GPS dans l'étude de la marche en extérieur et proposer une nouvelle méthode d'évaluation de la capacité de marche spontanée de patients présentant une AOMI.
58

The Mechanism of a BMP-Driven Mesenchymal-to-Epithelial Transition in the Reprogramming of Induced Pluripotent Stem Cells

Liu, Da 18 March 2014 (has links)
Somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) by the ectopic expression of defined factors. iPSCs hold great promise for pharmaceutical screening and regenerative medicine but the mechanism of reprogramming is not well understood. This work examines a component process of reprogramming that is the mesenchymal-to-epithelial transition (MET), an important step in the generation of iPS cells. In this thesis I demonstrate a connection between BMP signaling and the reprogramming factor Klf4 in the activation of the MET expression program. Using ChIP-Seq I mapped the binding of Klf4 and BMP Smads across the genome and linked their co-binding to a MET expression program determined by RNA-Seq. My work uncovers a thus-far unreported interaction between Klf4 and BMP signaling in cellular epithelialization that can directly improve the technical methods of reprogramming and have important implications for the induction of epithelial tissues in general.
59

The Mechanism of a BMP-Driven Mesenchymal-to-Epithelial Transition in the Reprogramming of Induced Pluripotent Stem Cells

Liu, Da 18 March 2014 (has links)
Somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) by the ectopic expression of defined factors. iPSCs hold great promise for pharmaceutical screening and regenerative medicine but the mechanism of reprogramming is not well understood. This work examines a component process of reprogramming that is the mesenchymal-to-epithelial transition (MET), an important step in the generation of iPS cells. In this thesis I demonstrate a connection between BMP signaling and the reprogramming factor Klf4 in the activation of the MET expression program. Using ChIP-Seq I mapped the binding of Klf4 and BMP Smads across the genome and linked their co-binding to a MET expression program determined by RNA-Seq. My work uncovers a thus-far unreported interaction between Klf4 and BMP signaling in cellular epithelialization that can directly improve the technical methods of reprogramming and have important implications for the induction of epithelial tissues in general.
60

Identifying Novel MicroRNA Enhancers of Somatic Cell Reprogramming

Corso, Andrew John 21 November 2013 (has links)
In addition to the well-characterized Induced Pluripotent Stem cells (iPSCs) that closely resemble Embryonic Stem cells (ESCs), a recent study has proven the existence of a stable state, resembling partially reprogrammed cells, termed F-class iPSCs. To study these distinct iPSC states, a reprogramming dataset has been generated, featuring the parallel analysis of multiple molecular platforms. MicroRNAs (miRNAs) are small RNA regulators of gene expression whose critical role in reprogramming is now being realized. In the present study, small RNA deep sequencing data from this novel reprogramming dataset was used to identify miRNAs that are likely to enhance reprogramming by detecting significantly up-regulated miRNAs in ESC-like iPSCs versus F-class iPSCs. These candidate miRNAs were cloned and overexpressed in reprogramming mouse embryonic fibroblasts and their effect on reprogramming efficiency was measured. miR-214 was discovered to increase iPSC generation efficiency, marking the first reprogramming-related role for this microRNA.

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