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

高密度脂蛋白相关蛋白酶抑制剂活性在预防动脉粥样硬化中的作用。

• 批准号: 9765384
• 负责人: Scott M Gordon
• 金额: $ 24.48万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-20 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765384
• 关键词: ATP binding cassette transporter 1; Active Biological Transport; Acute; Acute-Phase Reaction; Anti-inflammatory; Apolipoprotein E; Arterial Fatty Streak; Arteries; Atherosclerosis; Binding; Biological Assay; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Career Transition Award; Cause of Death; Cell Culture Techniques; Cholesterol; Complex; Coronary Angiography; Coronary Artery Bypass; Data; Developed Countries; Developing Countries; Development; Dimensions; Elastases; Endothelium; Event; Faculty; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Histologic; Human; Imaging Techniques; In Vitro; Individual; Inflammation; Inflammatory Response; Infusion procedures; LDL Cholesterol Lipoproteins; Label; Leukocyte Elastase; Lipids; Lipoprotein Binding; Maps; Mass Spectrum Analysis; Measures; Mediating; Mentors; Methionine; Methods; Morphology; Mus; Myocardial Infarction; National Heart, Lung, and Blood Institute; Oxides; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Plasma; Plasma Proteins; Population; Positioning Attribute; Postdoctoral Fellow; Production; Property; Protease Inhibitor; Protein Family; Proteins; Pulmonary Embolism; Reporting; Research; Residual state; Risk; Role; Rupture; Serine Proteinase Inhibitors; Site; Site-Directed Mutagenesis; Small Interfering RNA; Stroke; Structure; Testing; Therapeutic; Thrombus; Tissues; Transference; United States; United States National Institutes of Health; Universities; Untranslated RNA; Up-Regulation; Variant; Vascular Endothelium; Work; alpha 1-Antitrypsin; base; cardiovascular risk factor; crosslink; cytokine; elastase inhibitor; electron tomography; experience; experimental study; genetic variant; human subject; in vivo; knock-down; macrophage; member; men; molecular imaging; mouse model; neglect; neutrophil; novel; overexpression; oxidation; particle; peptidomimetics; preservation; prevent; protein degradation; protein function; public health relevance; reconstitution; research clinical testing; skills; study population; tenure track; tool; transcytosis; uptake

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.

项目概要和摘要 高密度脂蛋白（HDL）与以下事件的发生具有良好的负相关性： 心血管疾病然而，介导这种保护作用的HDL的功能活性是 没有很好地理解。HDL是由脂质和一系列不同的 这些蛋白质可能赋予携带它们的HDL颗粒特定功能。以上 在85个已鉴定的HDL相关蛋白中，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剂（SERPIN）家族的成员， proteins.这项建议将研究最丰富的HDL结合蛋白之间的结构相互作用， SERPIN、α-1-抗胰蛋白酶（A1AT）和HDL颗粒以及这一作用的功能后果 互动戈登博士将使用单个粒子电子断层扫描技术， 技术，以确定A1AT和HDL之间相互作用的结构细节，并确定 A1AT蛋白参与结合的区域。使用富含A1AT的重组HDL，Dr. 戈登将研究这些颗粒降低血管蛋白酶活性的能力， 随后在小鼠模型中动脉粥样硬化发展。此外，一种新的HDL靶向小 A1AT的肽模拟物将被开发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，努力防止血栓形成， 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的博士后研究员Scott Gordon博士提出的， 肺和血液研究所在美国国立卫生研究院，作为NHLBI K22职业的一部分 过渡奖。戈登博士进行了他的研究生研究的组成和功能的高密度脂蛋白 并在本提案中扩展了他以前的工作。由经验丰富的导师组成的团队， 戈登博士已经收集了与本提案各方面相关的各种技能，以协助 成功完成拟议的研究以及戈登博士的成功过渡 进入一个独立的终身教职轨道学术教师的立场，在一个主要的研究型大学， 美国的