Regulation of Pal-1 in Atherosclerosis and Thrombosis

描述（由申请人提供）：动脉粥样硬化是心血管疾病的主要原因，是美国死亡率和发病率的主要原因。与动脉粥样硬化相关的危险因素包括；型糖尿病。和高血压。血浆中丝氨酸蛋白酶抑制剂、纤溶酶原激活抑制剂-1 （PAI- 1）水平升高与这些危险因素和其他几种血栓性疾病相关。- - - - - -。纤维分解系统的主要调节者，并被牵连为；的主要参与者；在心血管疾病的病理生理学中，纤溶酶原激活物抑制剂-1包含三个主要功能域：1)活性位点区域；2)玻璃体连接蛋白结合位点；3)；ic-w-density.lipopr。Btein受体相关蛋白位点这些域，。共同或单独促成PAI-1在动脉粥样硬化和。血管疾病。我打算这么做。开发适合于。三个PAI-1功能域（SA I），并确定这些适体对内皮细胞功能的影响（SA II）。最后，我将评估他们的监管能力。血栓形成和血管生成；在体内，使用两种表征良好的小鼠模型系统（SA III）。我的研究计划/整合了我的。具有血管炎症的生物化学和分子生物学背景；活体动物研究；这将极大地促进我的长期职业目标，成为一个独立的调查员在…领域。”,-。止血和血栓形成。在接下来的五年里，我希望扩大我的基础科学。有血栓和凝血方面的知识。我也渴望提高我提出假设和设计实验来验证我的假设的能力，并获得更多的技术技能来进行体内动物研究。获得额外的知识。在这些方面将有利于我晋升为副教授。Charles Lowenstein博士是血管内皮功能领域公认的权威，他将为我的职业发展提供宝贵的指导。约翰霍普金斯大学及其庞大的机构和人力资源，为进行我所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·塞门扎博士和珍妮丝·克莱门茨博士组成，他们都在各自的领域表现出色，作为调查人员和导师，他们有着非凡的资质。相关性（见使用说明）：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，减少PAI-1的功能将是治疗和预防PAI-1相关血管事件的有益治疗选择。这一点尤其重要，因为到目前为止，还没有可用于临床的PAI-1抑制剂。

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)