p38alpha and beta MAP Kinases in Endothelial Cells

内皮细胞中的 p38α 和 β MAP 激酶

• 批准号: 6952937
• 负责人: YAN-LIN GUO
• 金额: $ 19.69万
• 依托单位: UNIVERSITY OF SOUTHERN MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952937
• 关键词: angiogenesis; angiogenesis factor; cell cell interaction; cell growth regulation; cell proliferation; collagen; enzyme activity; extracellular matrix; fibroblast growth factor; fluorescent dye /probe; gene expression profiling; immunoprecipitation; integrins; isozymes; mitogen activated protein kinase; tissue /cell culture; vascular endothelial growth factors; vascular endothelium; western blottings

DESCRIPTION (provided by applicant): Angiogenesis, the formation of new blood capillaries from preexisting vessels, is essential for normal physiological processes, such as wound healing and embryogenesis. It also occurs under pathological conditions, such as cancer, rheumatoid arthritis, and certain cardiovascular diseases. Vessel formation is a complex event controlled by multiple signaling pathways activated by angiogenic factors and by endothelial cell-matrix interaction. p38 MAP kinases are activated by angiogenic factors and by extracellular matrix proteins. Both in vivo and in vitro studies have shown that the p38 signaling pathway plays important roles in the regulation of angiogenesis. However, the mechanisms involved are not well defined. The goal of this research is to investigate the roles for p38alpha and p38beta, two major isoforms expressed in endothelial cells (ECs), in the regulation of EC activities involved in angiogenesis. To accomplish this goal, we will modulate the expression level and kinase activity of p38alpha and p38beta by adenovirus-mediated gene targeting technique. The specific functions of p38alpha and p38beta will be assessed in two different experimental systems: a) in 2-dimensional (2D) cell dishes where cell proliferation is the major activity of ECs, and b) in 3D collagen matrices where ECs differentiate into tube-like structures, mimicking the steps of vessel formation. The specific aims of this project are: 1) to test the hypothesis that angiogenic factors (bFGF and VEGF) and collagen matrix differentially activate p38alpha and p38beta, which may coordinately regulate vessel formation, 2) to determine the roles of p38alpha and p38beta in EC proliferation, survival, and morphogenesis, and 3) to test the hypothesis that the p38 pathway may serve as a molecular switch between proliferation and differentiation in 2D and 3D cell culture environments. We expect that the results obtained from the two different experimental systems will be complementary and lead to a better understanding of the signaling mechanisms of p38alpha and p38beta in the regulation of angiogenesis. This investigation may provide new knowledge to the development of novel therapeutic drugs for diseases associated with angiogenesis.

描述（由申请人提供）：血管生成，先前存在的血管的新血液毛细血管形成，对于正常的生理过程，例如伤口愈合和胚胎发生至关重要。它也发生在病理状况下，例如癌症，类风湿关节炎和某些心血管疾病。血管形成是一个复杂的事件，由由血管生成因子激活的多个信号通路和内皮细胞 - 矩阵相互作用控制。 P38 MAP激酶被血管生成因子和细胞外基质蛋白激活。体内和体外研究都表明，p38信号通路在血管生成的调节中起着重要作用。但是，所涉及的机制尚未很好地定义。这项研究的目的是研究p38alpha和p38beta的作用，这是在内皮细胞（EC）中表达的两个主要同工型（EC），在调节参与血管生成的EC活性中的作用。为了实现这一目标，我们将通过腺病毒介导的基因靶向技术调节p38alpha和p38beta的表达水平和激酶活性。将在两个不同的实验系统中评估p38alpha和p38beta的特定功能：a）在3D胶原蛋白基质中细胞增殖是EC的主要活性的二维（2D）细胞培养皿中，其中EC分别为管子 - 像结构一样，模仿了血管形成的步骤。该项目的具体目的是：1）检验以下假设：血管生成因子（BFGF和VEGF）和胶原蛋白矩阵差异激活p38alpha和p38beta，它们可能协调调节血管形成，2）确定p38alpha和p38alpha和p38beta在EC中的作用。增殖，生存和形态发生，以及3）检验p38途径可以作为2D和3D细胞培养环境中分化之间的分子切换的假设。我们预计从两个不同的实验系统获得的结果将是互补的，并可以更好地理解对血管生成调节中p38alpha和p38beta的信号传导机制。这项研究可能为与血管生成相关的疾病的新型治疗药物的开发提供新知识。