Regulation of Pal-1 in Atherosclerosis and Thrombosis

描述(申请人提供)：动脉粥样硬化是心血管疾病的主要原因，也是美国死亡率和发病率的主要贡献者。与动脉粥样硬化相关的危险因素包括；2型糖尿病。还有高血压。血浆丝氨酸蛋白酶抑制物、纤溶酶原激活物抑制物-1(PAI-1)水平的升高与这些危险因素和其他几种血栓性疾病相关。PAI-1是纤溶系统的主要调节因子，与心血管疾病的病理生理学有关，纤溶酶原激活物抑制物-1包含三个主要功能结构域：1)活性部位；2)玻璃体粘连蛋白结合部位；和3)。与脂蛋白受体相关的蛋白位点..‘这些结构域。共同或单独参与PAI-1‘S在动脉粥样硬化和血管疾病中的作用。我提议这样做。开发适配子。三个PAI-1功能区(SA I)，并确定这些适配子对内皮细胞功能(SA II)的影响。最后，我将使用两个具有良好特性的小鼠模型系统(SA III)在体内评估其调节血栓形成和血管生成的能力。我的研究建议/将我的生物化学和分子生物学背景与血管炎症相结合；以及活体动物研究。这将极大地促进我的长期职业目标，成为一名……领域的独立研究人员。‘，-.止血和血栓形成。在接下来的五年里，我希望扩大我在血栓形成和凝血领域的基础科学知识。我也渴望提高我开发假说和设计实验来检验我的假说的能力，以及获得更多的技术技能来进行活体动物研究。在这些方面获得更多的知识将有助于我晋升为副教授。查尔斯·洛文斯坦博士是公认的血管内皮细胞功能方面的权威，他将在我的职业发展过程中提供宝贵的指导。约翰·霍普金斯大学及其庞大的机构和人员资源为开展我建议的生物医学研究提供了理想的环境。我的顾问委员会由弗兰克·丘奇博士、格雷格·塞门扎博士和贾尼斯·克莱门茨博士组成，他们都在各自的领域表现出色，都拥有作为研究人员和导师的非凡资历。相关性(请参阅说明)：。了解PAI-1的生理功能及其在正常和病理条件下的作用机制，对于制定治疗和预防高危患者心血管事件的策略是必要的。因此，抑制纤溶酶原激活物-1的S功能将是治疗和预防纤溶酶原激活物-1相关血管事件的有益选择。这一点特别重要，因为到目前为止，还没有可用于临床的PAI-1抑制剂(摘要结束)

DESCRIPTION (provided by applicant): Atherosclerosis is the major cause of cardiovascular disease, which is the leading contributor to mortality and morbidity in the United States. Risk factors associated, with atherosclerosis include, ;type 2-diabetes. and hypertension. Elevated plasma levels of the serine protease inhibitor, plasminogen activatoMnhibitor-1, (PAI- 1) are correlated with these'risk factors and:several other thrombotic disorders..PAI-1.is the-.main regulator of the fibriholysis system, and is implicated as';a major player in the; pathopnysiology of cardiovascular disease, Plasminogen activator inhibitor-1 contains three major functional domains: 1) the.active.site region; 2) the vitronectin binding site;, and 3). the; ic-w-density.lipopr.btein receptor related protein site..'these domains , . contribute either jointly or individually to PAI-1's role, in atherosclerosis and.vascular disease. I propose to. develop aptamers to. the three PAI-1 functional domains (SA I), and determine the effects, of these aptamers on endothelial cell function (SA II). Finally, I will assessIheir ability to regulate .thrombosis and angiogenesis ; in vivo, using two well characterized mouse model systems (SA III). My research proposal/integrates my., background in biochemistry and molecular biology with vascular inflammation;and..in vivo animal studies.; This will greatly facilitate my long term career goal to become an independent investigator in the .field of . ',-. hemostasis and thrombosis. Over the next five years, I wish to expand my basic'science.knowledge in the area of thrombosis and coagulation. I also aspire to improve my ability to develop hypotheses and design experiments to test my hypotheses, as well as to acquire more technical skills to conduct in vivo animal studies. Gaining additional knowledge.;in these areas will facilitate my promotion to associate professor. Dr. Charles Lowenstein, a widely recognized authority on vascular endothelial function will provide invaluable mentorship throughout my career development. John Hopkins University and its vast institutional and personnel resources, provides an ideal setting in which to conduct the biomedical research I propose. My advisory committee consists of Dr. Frank Church, Dr. Gregg Semenza, and Dr. Janice Clements, all of whom have excelled in their fields and who have exceptional credentials as investigators and mentors. RELEVANCE (See instructions): . Understanding the physiological function of PAI-1, and the mechanism underlying its function under normal and pathological conditions, is necessary to develop strategies to treat and prevent cardiovascular events in high risk patients. Consequently, abatement of PAI-1's function will be a beneficial therapeutic option for the treatment and prevention of PAI-1 associated vascular events. This is particularly important, since to date, there are no PAI-1 inhibitors available for clinical use (End of Abstract)