Signal Transduction in Atherosclerosis

描述(由申请人提供)：这个高度整合的项目专注于研究影响离散区域动脉粥样硬化易感性的因素。机械力和化学介质对血小板、血管和管壁细胞的相互作用以及它们与细胞外基质的相互作用的复杂相互作用将被阐明。不同和重叠的信号通路将通过对动脉粥样硬化易感性和保护性之间平衡的决定因素的基因组和蛋白质组询问来整合。将特别注意包括年龄、高脂血症和性别在内的传统危险因素如何影响与炎症和细胞周期相关的细胞信号通路。在项目1中，将评估COX-2和mPGES-1的作用。新的小鼠模型将描绘它们在血管内皮细胞、血管平滑肌细胞、巨噬细胞和心肌细胞对心血管功能的贡献。先验假设检验将补充无偏见的方法，以评估酶破坏对离散表型和生物网络的影响。在项目4中，将通过细胞特异性缺失和COX-2的强制表达、IP的缺失、拮抗和刺激，以及通过生物物理方法评估对细胞外基质的不同影响，来探讨ApoE/COX-2/PGl2/IP途径与细胞周期的相互作用。最后，在项目5中，我们将研究性别和高脂血症对从猪动脉易患动脉粥样硬化和防止动脉粥样硬化形成的区域获得的内皮细胞基因组亚群离散表达的影响。这项计划将采取综合的方法来研究血管细胞中的体液和机械信号。这种相互作用的细胞间异质性的基础因素可能有助于动脉粥样硬化形成的局灶性。

DESCRIPTION (provided by applicant): This highly integrated program is focused on the study of factors influencing discrete regional susceptibility to atherogenesis. The complex interplay of mechanical forces and chemical mediators which impinge on platelet vascular interactions and on cells of the vessel wall and their interaction with the extracellular matrix will be elucidated. Distinct and overlapping signaling pathways will be integrated by genomic and proteomic interrogation of determinants of the balance between susceptibility to and protection from atherosclerosis. Particular attention will be paid to how traditional risk factors, including age, hyperiipidemia and gender condition cell signaling pathways of relevance to inflammation and the cell cycle. In Project 1 the role of COX-2 and mPGES-1, will be assessed. Novel mouse models will delineate their contribution in endothelial, vascular smooth muscle cells, macrophages and cardiomyocytes to cardiovascular function. A priori hypothesis testing will complement unbiased approaches to assess the impact of enzyme disruption on discrete phenotypes and biological networks. In Project 4 the interaction between the ApoE/COX-2/PGl2/IP pathway and the cell cycle will be probed, using cell specific deletions and forced expression of COX-2, deletion, antagonism and stimulation of the IP and by using biophysical approaches to assess differential impact on the extracellular matrix. Finally, in Project 5 we shall examine the effect of gender and hyperiipidemia on the discrete expression of genomic subsets in endothelial cells obtained from regions of the pig aorta susceptible to and protected from atherogenesis. This program will take an integrated approach to the study of humoral and mechanical signaling in vascular cells. Factors that underlie the cell to cell heterogeneity of this interaction are likely to contribute to the focal nature of atherogenesis.