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。

基本信息

批准号：
9983143
负责人：
Scott M Gordon
金额：
$ 24.06万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-20 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9983143
关键词：
ATP binding cassette transporter 1 Active Biological Transport Acute Acute-Phase Reaction Anti-Inflammatory Agents 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 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

项目摘要

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）与以下疾病的发生具有明确的负相关性：心血管疾病。然而，介导这种保护的 HDL 功能活动是不太理解。 HDL 是由脂质和一系列不同的物质组成的胶束复合物蛋白质可能赋予携带它们的高密度脂蛋白颗粒特定的功能。更多超过 85 种已识别的 HDL 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剂 (SERPIN) 家族的成员蛋白质。该提案将检查最丰富的 HDL 结合体之间的结构相互作用 SERPIN、α-1-抗胰蛋白酶 (A1AT) 和 HDL 颗粒以及其功能后果相互作用。戈登博士将使用单粒子电子断层扫描，一种新颖的分子成像技术，以确定 A1AT 和 HDL 之间相互作用的结构细节，并识别 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和随后在小鼠模型中发生动脉粥样硬化。此外，一种针对小 A1AT 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并稳定现有斑块，以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中心博士后研究员 Scott Gordon 博士提出的，美国国立卫生研究院肺和血液研究所，作为 NHLBI K22 职业的一部分过渡奖。 Gordon 博士对 HDL 的组成和功能进行了研究生研究并在当前提案中扩展了他之前的工作。经验丰富的导师团队戈登博士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美国一所主要研究型大学的独立终身教职学术教职美国。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Protease Activity in Vascular Disease.

DOI：
10.1161/atvbaha.119.312413
发表时间：
2019-09
期刊：
Arteriosclerosis, Thrombosis, & Vascular Biology
影响因子：
0
作者：
Megan Slack;S. Gordon
通讯作者：
Megan Slack;S. Gordon

Enhancement of High-Density Lipoprotein-Associated Protease Inhibitor Activity Prevents Atherosclerosis Progression.

增强高密度脂蛋白相关蛋白酶抑制剂活性可预防动脉粥样硬化进展。

DOI：
10.1101/2023.08.07.551670
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Mobilia,Maura;Karakashian,Alexander;Whitus,Callie;Neupane,KhagaR;Johnson,LanceA;Graf,GregoryA;Gordon,ScottM
通讯作者：
Gordon,ScottM