Lysolipid Signaling in Cardovascular Disease

描述(由申请人提供)： 血栓和炎性介质都促进了血管疾病的发展。众所周知，血小板通过导致急性血栓形成事件在缺血性心脏病和中风中发挥重要作用，也会在血管系统内释放强有力的炎症介质。溶血磷脂酸(LPA)是一种由血小板产生的生物活性脂质介质，在人类动脉粥样硬化斑块中大量存在。LPA通过特定的细胞表面G蛋白偶联受体(LPA1-3)刺激血小板、白细胞、内皮细胞和平滑肌细胞，调节细胞的生长、分化、存活、运动和收缩活动。LPA也可能是核过氧化物酶体增殖物激活受体γ(PPARγ)的激动剂。因此，LPA有望成为炎症反应和血栓反应的关键介质，并成为血管细胞功能的病理生理调节因子。本应用的目的是确定LPA在动脉粥样硬化性血栓性血管疾病相关事件中的生理学作用，并确定涉及的LPA受体(S)。我们的中心假设是，部分由激活的血小板产生的LPA刺激中膜SMC的表型改变，这些反应调节血管张力，并在动脉损伤后和动脉粥样硬化的背景下促进内膜增生的发展。我们建议通过结合细胞、药理学和功能基因组学方法来验证我们的假设，以达到以下三个特定目标：(1)确定LPA在血管损伤反应中的病理作用；(2)确定介导培养的血管SMC表型调节的LPA受体；(3)确定LPA受体在调节血管张力中的作用。为了实现我们的目标，我们将使用三个已知的G蛋白偶联LPA受体(LPA1-3)缺乏的小鼠，LPA1-3的新型药理亚型选择性激动剂和激动剂，以及具有取消配体结合的PPAR伽马突变的小鼠。我们的结果将为LPA信号通路在血管生理学和病理学中的作用提供具体的见解，并可能为动脉粥样硬化血栓形成障碍的治疗和预防提供新的靶点。

DESCRIPTION (provided by applicant): Both thrombotic and inflammatory mediators contribute to the development of vascular disease. Blood platelets, which are known to play an essential role in ischemic heart disease and stroke by contributing to acute thrombotic events, also release potent inflammatory agents within the vasculature. Lysophosphatidic acid (LPA) is a bioactive lipid mediator that is produced by platelets and found in abundance in human atherosclerotic plaques. LPA stimulates platelets, leukocytes, endothelial cells, and smooth muscle cells by acting through specific cell surface G-protein coupled receptors (LPA1-3) to regulate cell growth, differentiation, survival, motility, and contractile activity. LPA may also be an agonist for the nuclear peroxisome proliferator-activated receptor gamma (PPARgamma). Thus, LPA is poised to serve as a key mediator of both inflammatory and thrombotic responses and to be a pathophysiologic regulator of vascular cell function. The objective of this application is to determine the physiologic contribution of LPA to events that are relevant to atherothrombotic vascular disease and to identify the LPA receptor(s) involved. Our central hypothesis is that LPA generated, in part, by activated platelets stimulates phenotypic modulation of medial SMCs and that these responses regulate vascular tone and contribute to the development of intimal hyperplasia after arterial injury and in the setting of atherosclerosis. We propose to test our hypothesis by integrating cellular, pharmacologic and functional genomics approaches in the following three specific aims (1) establish a pathologic role for LPA in the vascular response to injury; (2) identify LPA receptors that mediate phentypic modulation of cultured vascular SMCs; (3) Identify the role of LPA receptors in the regulation of vascular tone. To accomplish our goals, we will use mice deficient in the three known G-protein coupled LPA receptors (LPA1-3), novel pharmacologic sub-type selective agonists and agonistists of LPA1-3, and mice with a PPARgamma mutation that abolishes ligand binding. Our results will provide specific insights into the role of LPA signaling pathways in vascular physiology and pathology and may provide novels targets for the treatment and prevention of atherothrombotic disorders.