Impact of Dysfunctional HDL on Platelet Function and in vivo Thrombosis

HDL 功能失调对血小板功能和体内血栓形成的影响

基本信息

批准号：
9893896
负责人：
WENLIANG SONG
金额：
$ 15.88万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9893896
关键词：
Acute Address Adverse effects Affect Agonist Aldehydes Anti-Inflammatory Agents Antiatherogenic Apoptosis Apoptotic Atherosclerosis Biology Bleeding time procedure Blood Blood Platelets Cardiovascular Diseases Cardiovascular system Career Choice Cholesterol Chronic Clinical Trials Controlled Study Coronary Arteriosclerosis Data Development Diabetes Mellitus Dyslipidemias Endothelial Cells Endothelium Environment F2-Isoprostanes Familial Hypercholesterolemia Fostering Functional disorder Funding Goals High Density Lipoprotein Cholesterol High Density Lipoproteins Human Impairment In Vitro Incubated Investigation K-Series Research Career Programs LDL Cholesterol Lipoproteins Lipid Peroxidation Low-Density Lipoproteins Malondialdehyde Mediation Medicine Mentors Mentorship Metabolism Modeling Modification Mus Oxidative Stress Oxides Patients Phenotype Physicians Plasma Platelet Activation Platelet aggregation Principal Investigator Property Research Research Personnel Risk Rodent Model Role Scientist Series Signal Transduction Testing Therapeutic Thrombosis Thromboxane Production Time Training Universities Very low density lipoprotein atherothrombosis cardioprotection career design hypocholesterolemia improved in vivo in vivo Model innovation insight lipid metabolism macrophage mouse model multidisciplinary novel oxidant stress oxidative damage peroxidation platelet function premature prevent public health relevance response reverse cholesterol transport thrombogenesis

项目摘要

PROJECT SUMMARY/ABSTRACT The studies outlined in this proposal will explore novel mechanisms by which dysfunctional high-density lipoprotein (HDL) impairs platelet function and promotes the prothrombotic phenotype and will test an innovative potential therapeutic strategy to reduce atherothrombosis. This proposal is for a Mentored Career Development Award by Dr. Wenliang Song in the Division of Cardiovascular Medicine of the Department of Medicine at Vanderbilt University. Dr. Song has a long-term career goal of being an independently funded physician-scientist focused on the role of lipid metabolism in cardiovascular disease. He has already invested heavily in this career path. He has extensive research background on lipoperoxidation and oxidative stress, platelet biology and rodent models of cardiovascular diseases. Recent evidence suggests that HDL function may be a better indicator than HDL cholesterol (HDL-C). Mounting evidence supports the concept that dysfunctional HDL, for example, oxidized HDL, loses its beneficial properties and actually contributes to the development of cardiovascular disease. Preliminary data in this proposal suggest that HDL from patients with Familial Hypercholesterolemia (FH) is enriched with peroxidation products, including malondialdehyde (MDA) and isolevuglandins(IsoLG), and is strikingly dysfunctional. Novel aldehyde scavengers, which targeted mitigate the adverse effects of reactive oxidative stress(ROS) without abrogating normal signaling of ROS, can reduce the peroxidation modification of the HDL and prevent formation of dysfunctional HDL. Previous studies suggest normal HDL can reduce agonist- stimulated platelet activation and aggregation, while oxidized HDL enhances platelet aggregation, yet the mechanisms are not clear. Interestingly, recent studies demonstrated that apoptosis also occurs in anucleate platelets, and apoptotic platelets accelerate in vivo arterial thrombosis formation. It is known that normal HDL is anti-apoptotic and oxidized HDL is pro-apoptotic in macrophages and endothelial cells, but no studies have ever investigated HDL’s effect on platelets apoptosis. Dr. Song hypothesizes that dysfunctional HDL, such as oxidized HDL and HDL from FH patient (FH-HDL), increase platelet activation in vivo leading to enhance thrombosis through inducing apoptosis. The effect of peroxidation modification of HDL, as well as FH-HDL, on platelet apoptosis and activity will be tested. Two in vivo thrombosis mouse models (acute and chronic) will also be used. Wild type, LDLr-/- and ApoA1-/-LDLr-/- mice will be used to mimic the FH condition, and to assess the contribution of HDL. Novel aldehyde scavengers will be used to protect HDL from dysfunction and rescue the phenotypes. This proposed research will provide novel insights into the impact of HDL on platelet biology and advance the field of HDL function in atherothrombosis. The principal investigator has assembled a multidisciplinary mentorship committee. He and his mentor have outlined a detailed well thought training plan. He will have 80% protected time for research. Vanderbilt offers an exceptional environment and strong institutional commitment to foster this candidate's transition to becoming an independent investigator.

项目概要/摘要本提案中概述的研究将探索功能失调的高密度细胞的新机制脂蛋白（HDL）损害血小板功能并促进血栓前表型，将测试一种创新的减少动脉粥样硬化血栓形成的潜在治疗策略该提案旨在指导职业发展。医学部心血管内科宋文亮博士获奖范德比尔特大学。宋博士的长期职业目标是成为一名独立资助的医师科学家。他专注于脂质代谢在心血管疾病中的作用，他已经在这一事业上投入了大量资金。他在脂过氧化和氧化应激、血小板生物学和啮齿动物方面拥有广泛的研究背景。最近的证据表明，HDL 功能可能是一个更好的指标。高密度脂蛋白胆固醇 (HDL-C) 越来越多的证据支持功能失调的高密度脂蛋白 (HDL) 会被氧化的概念。 HDL 失去其有益特性，实际上会导致心血管疾病的发展。该提案中的初步数据表明，家族性高胆固醇血症 (FH) 患者的 HDL 是富含过氧化产物，包括丙二醛 (MDA) 和异黄酮 (IsoLG)，新型醛清除剂，其目标是减轻反应性的不利影响。氧化应激（ROS）而不消除ROS的正常信号传导，可以减少过氧化修饰先前的研究表明，正常的 HDL 可以减少激动剂- 刺激血小板活化和聚集，而氧化 HDL 则增强血小板聚集，但隐含机制尚不清楚，最近的研究表明细胞凋亡也发生在无核细胞中众所周知，正常HDL是血小板和凋亡血小板加速体内动脉血栓的形成。抗凋亡和氧化的 HDL 在巨噬细胞和内皮细胞中具有促凋亡作用，但尚无研究表明宋英雄博士研究了HDL对血小板凋亡的影响，认为HDL功能失调，例如氧化。 HDL 和 FH 患者的 HDL (FH-HDL) 增加体内血小板活化，导致血栓形成通过诱导细胞凋亡 HDL 以及 FH-HDL 的过氧化修饰对血小板的影响。还将使用两种体内血栓形成小鼠模型（急性和慢性）来测试细胞凋亡和活性。野生型、LDLr-/- 和 ApoA1-/-LDLr-/- 小鼠将用于模拟 FH 状况，并评估新型醛清除剂的贡献将用于保护 HDL 免受功能障碍并挽救。这项拟议的研究将为 HDL 对血小板生物学和表型的影响提供新的见解。推进 HDL 在动脉粥样硬化血栓形成中的功能领域的研究进展他和他的导师制定了一份经过深思熟虑的详细培训计划。他将有 80% 的受保护时间用于研究。范德比尔特提供了优越的环境和强大的实力。促进该候选人过渡为独立调查员的机构承诺。