The Role of High Density Lipoprotein Associated Protease Inhibitor Activity in Protection Against Atherosclerosis.

项目摘要和摘要 高密度脂蛋白(HDL)与高血压的发生有明确的负相关关系。 心血管疾病。然而，调节这种保护的高密度脂蛋白的功能活动是 不是很清楚。高密度脂蛋白是由脂类和一系列不同的 可能赋予携带它们的高密度脂蛋白颗粒特定功能的蛋白质。更多 超过85个已鉴定的高密度脂蛋白相关蛋白，超过20%具有与蛋白酶相关的已知功能 抑制，其中大多数是丝氨酸蛋白酶抑制物(SERPIN)家族的成员 蛋白质。这一建议将研究最丰富的高密度脂蛋白结合的结构相互作用 SERPIN、α-1-抗胰蛋白酶(A1AT)和高密度脂蛋白颗粒及其功能后果 互动。戈登博士将使用单个粒子电子断层扫描，这是一种新的分子成像技术 技术，以确定A1AT和高密度脂蛋白相互作用的结构细节并识别 参与结合的A1AT蛋白区域。使用重组的高密度脂蛋白，富含A1AT，Dr。 戈登将研究这些颗粒降低血管蛋白酶活性的能力，并 在小鼠模型中随后的动脉粥样硬化的发展。此外，一种新的针对小尺寸的高密度脂蛋白 将开发A1AT的多肽模拟物，并评估其预防动脉粥样硬化的能力 发展和稳定现有的斑块，以努力防止血栓形成和 随后的心血管事件，如心脏病发作、中风或肺栓塞。 这项工作是由国家心脏博士后研究员斯科特·戈登博士提出的， 国立卫生研究院肺和血液研究所，作为NHLBI K22职业生涯的一部分 过渡奖。戈登博士对高密度脂蛋白的组成和功能进行了研究生研究 并在目前的提案中扩展了他之前的工作。一支经验丰富的导师团队，拥有 戈登博士已经收集了与该提案的各个方面相关的各种技能，以帮助 成功完成拟议的研究以及戈登博士的成功过渡 进入独立终身教职轨道的一所主要研究型大学的教职 美国。

Project Summary and Abstract High density lipoproteins (HDL) have a well-established inverse correlation with the occurrence of cardiovascular disease. However, the functional activities of HDL which mediate this protection are not well understood. HDL are micellar complexes composed of lipids and an array of different proteins which are likely to confer specific functions to the HDL particles that carry them. Of more than 85 identified HDL associated proteins, over 20% have known functions related to protease inhibition, the majority of these are members of the Serine Protease Inhibitor (SERPIN) family of proteins. This proposal will examine the structural interaction between the most abundant HDL-bound SERPIN, alpha-1-antitrypsin (A1AT), and HDL particles and also the functional consequences of this interaction. Dr. Gordon will use individual particle electron tomography, a novel molecular imaging technique, to determine the structural details of the interaction between A1AT and HDL and to identify the region of the A1AT protein involved in binding. Using reconstituted HDL, enriched with A1AT, Dr. Gordon will investigate the capacity of these particles to reduce vascular protease activity and subsequent atherosclerosis development in a mouse model. Additionally, a novel HDL targeting small peptide mimetic of A1AT will be developed and evaluated for its capacity to prevent atherosclerosis development and to stabilize existing plaque in an effort to prevent thrombus formation and subsequent cardiovascular events such as heart attack, stroke, or pulmonary embolism. This work has been proposed by Dr. Scott Gordon, a postdoctoral fellow of the National Heart, Lung, and Blood Institute at the National Institutes of Health, as part of an NHLBI K22 Career Transition Award. Dr. Gordon performed his graduate studies on the composition and function of HDL and has extended his previous work in the current proposal. A team of experienced mentors with a variety of skills related to aspects of this proposal has been assembled by Dr. Gordon to assist in the successful completion of the proposed research as well as the successful transition of Dr. Gordon into an independent tenure track academic faculty position at a major research university in the United States.