Novel Targets in Thrombosis and Atherosclerosis

描述(由申请人提供)： 动脉粥样硬化和血管疾病的发展是一个多方面的过程，涉及遗传和环境因素，这些因素以复杂的方式相互作用。这些不同因素在任何个体身上的独特相互作用都可以促进特定生理途径的失调，进而影响其他生理系统。这个项目将探索三个主要生理系统之间的边界，这些系统与血管疾病的关系已经确立。这些系统是：血栓形成/纤溶、炎症和脂质代谢，每个系统都与血管疾病的发展独立相关。最近的研究表明，这些系统中的每一个在血管疾病的发展中所起的作用可能不是相互独立的，并且这三个系统之间以前未被认识到的相互作用或“串扰”可以极大地影响疾病的进展。例如，血栓形成既可引发急性血管事件，又可引发血管床的长期变化，从而导致缺血性疾病的发展。炎症反过来会促进血栓形成，而高脂血症则会促进炎症。然而，除了这些已知的相关性，新的数据开始显示跨越这三个系统的特定分子相互作用。纤溶酶原激活物抑制物-1(PAI-1)是一种在炎症和血栓形成中都起作用的分子，最近的数据表明PAI-1也可能在调节脂质代谢中发挥作用。因此，这项应用将创建一个综合程序，测试特定分子事件调节血栓形成、炎症和脂代谢之间的串扰这一假设，这些因素显著影响血管疾病的进展。每个项目都基于每个研究人员的不同优势，并试图确定这些不同系统之间的特定相互作用点，然后描述与这些相互作用相关的特定分子事件。此应用程序由4个项目和三个核心组成，以支持这些项目。每个项目的主要目标是：项目1-表征PAI-1在脂质代谢中的作用；项目2-研究PAI-1在静脉血栓形成中的作用；项目3-研究冠状动脉移植血管病变中的血栓/纤溶平衡；以及项目4-确定斑马鱼中的血栓形成修饰物基因和新型抗凝剂。这些目标的成功实现将导致更好地了解血管疾病的病因，并最终改进血栓形成和血管疾病的治疗。

DESCRIPTION (provided by applicant): The development of atherosclerosis and vascular disease is a multifaceted process that involves both genetic and environmental factors which interact in complex ways. The unique interactions of these different factors in any individual can promote the dysregulation of specific physiologic pathways, which in turn can then affect other physiologic systems. This program project will explore the boundary between three prominent physiologic systems whose involvement in vascular disease is well established. These systems are; thrombosis/fibrinolysis, inflammation, and lipid metabolism, and each has been independently linked with the development of vascular disease. More recent studies have suggested that the roles that each of these systems play in the development of vascular disease may not be independent of one another and that previously unrecognized interactions or "cross-talk" between these three systems can dramatically influence disease progression. For example, thrombosis can both provoke acute vascular events, and initiate longterm changes in the vascular bed that lead to the development of ischemic disease. Inflammation, in turn, is known to promote thrombosis, while hyperlipidemia is known to promote inflammation. However, beyond these known correlations new data are beginning to show specific molecular interactions that span these three systems. One molecule in particular that has been identified as playing a role in both inflammation and thrombosis is plasminogen activator inhibitor-1 (PAI-1), and very recent data suggests that PAI-1 may also play a role in regulating lipid metabolism. Therefore, this application will create an integrated program that will test the hypothesis that specific molecular events regulate cross-talk between thrombosis, inflammation, and lipid metabolism that significantly influence vascular disease progression. Each project is based on the diverse strengths of each of the investigators and seeks to identify specific points of interaction between these varied systems, and then to characterize the specific molecular events associated with these interactions. This application consists of 4 projects and three cores to support these projects. The primary goals of each project are: project 1- characterize the role of PAI-1 in lipid metabolism; project 2- examine the role of PAI-1 in venous thrombogenesis; project 3- investigate the thrombotic/fibrinolytic balance in coronary transplant vasculopathy; and project 4- Identify thrombosis modifier genes and novel anticoagulants In zebrafish. The successful implementation of these goals should lead to a better understanding of the etiology of vascular disease and ultimately to improved treatments of thrombosis and vascular disease.