Lysolipid Signaling in Cardovascular Disease

描述（由申请人提供）： 血栓形成和炎症介质都有助于血管疾病的发展。已知血小板通过促成急性血栓形成事件而在缺血性心脏病和中风中发挥重要作用，其也在脉管系统内释放强效炎性因子。 溶血磷脂酸（LPA）是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通过特异性细胞表面G蛋白偶联受体（LPA 1 - 3）调节细胞生长、分化、存活、运动和收缩活性来刺激血小板、白细胞、内皮细胞和平滑肌细胞。LPA也可以是核过氧化物酶体增殖物激活受体γ（PPARgamma）的激动剂。 因此，LPA有望作为炎症和血栓形成反应的关键介质，并成为血管细胞功能的病理生理调节剂。 本申请的目的是确定LPA对动脉粥样硬化血栓形成性血管疾病相关事件的生理作用，并鉴定相关的LPA受体。 我们的中心假设是，LPA产生的，部分地，由活化的血小板刺激表型调制的中膜SMC和这些反应调节血管张力，并有助于动脉损伤后内膜增生的发展和动脉粥样硬化的设置。 我们建议通过整合细胞，药理学和功能基因组学方法来验证我们的假设，具体目标如下：（1）建立LPA在血管损伤反应中的病理作用;（2）鉴定介导培养血管SMC表型调节的LPA受体;（3）鉴定LPA受体在血管张力调节中的作用。 为了实现我们的目标，我们将使用三种已知G蛋白偶联LPA受体（LPA 1 - 3）缺陷的小鼠、LPA 1 - 3的新型药理学亚型选择性激动剂和激动剂，以及具有消除配体结合的PPARgamma突变的小鼠。 我们的研究结果将为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疾病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.