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P38alpha in Mouse Embryonic Stem Cells

小鼠胚胎干细胞中的 P38alpha

基本信息

批准号：
7268132
负责人：
YAN-LIN GUO
金额：
$ 21.26万
依托单位：
UNIVERSITY OF SOUTHERN MISSISSIPPI
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-31 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7268132
关键词：
3-Dimensional Abnormal Endothelial Cell Affect Animal Model Biological Assay Blood Vessels Cardiovascular system Cell Adhesion Cell Differentiation process Cell Lineage Cell Proliferation Cell physiology Cells Collagen Defect Depth Development Disease ES Cell Line Embryo Embryonic Development Endothelial Cells Family Genes Goals Growth and Development function In Vitro Investigation Knock-out Knockout Mice Knowledge Link MAPK14 gene Mammalian Cell Mitogen-Activated Protein Kinases Mitogens Modeling Molecular Morphogenesis Morphology Mus Nature Physiological Processes Physiology Property Protein Isoforms Protein Kinase Proteins Range Regulation Role Series Somatic Cell Stimulus Structure System Testing Therapeutic Tube Vascular System Vascularization angiogenesis base cell type embryonic stem cell human MAPK14 protein in vivo leukemia inhibitory factor novel prevent stem tool

项目摘要

DESCRIPTION (provided by applicant): p38 mitogen activated protein (MAP) kinases are widely expressed protein kinases that regulate growth and development. p38alpha is the most abundant isoform expressed in mammalian cells. Depending on cell types and the nature of stimuli, p38alpha regulates a wide range of physiological processes, such as cell proliferation, survival, and differentiation. Its pivotal role in embryogenesis is best demonstrated in p38alpha knockout (p38a-/-) mice where embryos display defective vascularization and vessel structures, suggesting a critical role of p38alpha in the development of vascular system. p38alpha knockout is lethal, thus limited information can be obtained from animal models. However, the embryonic stem (ES) cells isolated from knockout embryos (p38a-/-ES cells) are viable, which can be a valuable cell system to analyze the specific functions of p38alpha. p38alpha has been intensively studied in somatic cells, but we know little of its functions in ES cells. We have shown that p38a-/-ES cells display several altered properties from wild type ES cells, including cell adhesion, morphology and viability. The goals of this proposal are: 1. to further characterize several lines of p38a and p38a-/-ES cells and to determine the molecular mechanisms underlying the altered properties of ES cells caused by p38alpha deletion, 2. to investigate the role of p38alpha in ES differentiation, specifically focusing on how the ability of ES cells to differentiate to endothelial cells (ECs) is affected in p38a-/-ES cell, and 3. to analyze ES cell-differentiated EC function by an 3-dimendsional (3D) in vitro angiogenesis model. In this model, ECs will be cultured in a 3D collagen matrix, where they undergo a series of morphological changes to form tube-like structures, mimicking the steps of in vivo blood vessel formation. This novel assay will be used as a functional analysis to test hypothesis that ECs derived from p38a-/-ES cells may retain certain abilities to differentiate, but differentiated cells may have impaired functions to assemble into normal vessels. This study is expected to provide well characterized and genetically defined pSSalpha deficiency ES cell lines, which will be particularly useful for in-depth investigation of the roles of pSSalpha in ES cell differentiation and vascular development. The knowledge derived from this study could be valuable for the development of cell-based therapeutic approaches for diseases associated with angiogenesis and cardiovascular malfunction.

描述（由申请人提供）：p38丝裂原活化蛋白（MAP）激酶是广泛表达的调节生长发育的蛋白激酶。p38 α是在哺乳动物细胞中表达最丰富的亚型。根据细胞类型和刺激的性质，p38alpha调节广泛的生理过程，如细胞增殖、存活和分化。其在胚胎发生中的关键作用在p38α敲除（p38a-/-）小鼠中得到了最好的证明，其中胚胎显示有缺陷的血管形成和血管结构，这表明p38α在血管系统发育中的关键作用。P38alpha基因敲除是致命的，因此从动物模型中获得的信息有限。然而，从基因敲除胚胎中分离的胚胎干细胞（p38a-/-ES细胞）是有活力的，这可以作为分析p38α特异性功能的有价值的细胞系统。p38 α在体细胞中的研究已经深入，但我们对其在胚胎干细胞中的功能知之甚少。我们已经证明p38a-/-胚胎干细胞表现出与野生型胚胎干细胞不同的一些特性，包括细胞粘附、形态和活力。本提案的目标是：1。为了进一步表征p38a和p38a-/-胚胎干细胞系，并确定p38α缺失导致胚胎干细胞特性改变的分子机制，2。2 .研究p38α在ES分化中的作用，特别关注p38a-/-ES细胞如何影响ES细胞向内皮细胞（ECs）分化的能力；通过三维体外血管生成模型分析ES细胞分化的EC功能。在该模型中，内皮细胞将在3D胶原基质中培养，在那里它们经历一系列形态变化形成管状结构，模仿体内血管形成的步骤。这项新实验将被用作功能分析，以验证来自p38a-/- es细胞的ECs可能保留一定的分化能力，但分化的细胞可能会损害组装成正常血管的功能。该研究有望提供pSSalpha缺陷的胚胎干细胞系，这将对深入研究pSSalpha在胚胎干细胞分化和血管发育中的作用特别有用。从这项研究中获得的知识可能对开发与血管生成和心血管功能障碍相关的疾病的基于细胞的治疗方法有价值。