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

• 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
• 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

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.

项目总结/摘要 这项提案中概述的研究将探索功能失调的高密度脑血管病的新机制。 脂蛋白（HDL）损害血小板功能，促进血栓形成前表型，并将测试一种创新的 减少动脉粥样硬化血栓形成的潜在治疗策略。本提案旨在进行辅导职业发展 医学部心血管内科宋文良医生颁发的奖项， 范德比尔特大学。宋博士有一个长期的职业目标是成为一个独立资助的医生科学家 主要研究脂质代谢在心血管疾病中的作用。他已经在这个职业上投入了大量资金 路径他在脂质过氧化和氧化应激、血小板生物学和啮齿动物方面有广泛的研究背景 心血管疾病的模型。最近的证据表明，HDL功能可能是一个比 HDL胆固醇（HDL-C）。越来越多的证据支持功能失调的HDL的概念，例如，氧化 高密度脂蛋白，失去其有益的特性，实际上有助于心血管疾病的发展。 该提案的初步数据表明，家族性高胆固醇血症（FH）患者的HDL 富含过氧化产物，包括丙二醛（MDA）和异evuglandins（IsoLG）， 功能异常新型醛清除剂，其靶向减轻反应性醛的不利影响， 氧化应激（ROS）不废除ROS的正常信号转导，可以减少过氧化修饰， 并防止功能失调HDL的形成。以前的研究表明，正常的HDL可以减少激动剂- 刺激血小板活化和聚集，而氧化的HDL增强血小板聚集，然而， 机制尚不清楚。有趣的是，最近的研究表明，细胞凋亡也发生在无核细胞， 血小板和凋亡血小板加速体内动脉血栓形成。众所周知，正常的HDL是 抗凋亡和氧化的HDL在巨噬细胞和内皮细胞中是促凋亡的，但没有研究表明 观察HDL对血小板凋亡的影响。宋博士假设，功能失调的HDL，如氧化 HDL和来自FH患者的HDL（FH-HDL），增加体内血小板活化，导致血栓形成增加 通过诱导细胞凋亡。HDL及FH-HDL过氧化修饰对血小板的影响 检测细胞凋亡和活性。还将使用两种体内血栓形成小鼠模型（急性和慢性）。 将使用野生型、LDLr-/-和ApoA 1-/-LDLr-/-小鼠来模拟FH状况，并评估FH的耐受性。 HDL的贡献。新的醛清除剂将用于保护HDL功能障碍，并拯救HDL。 表型这项拟议的研究将为HDL对血小板生物学的影响提供新的见解， 推进动脉粥样硬化血栓形成中HDL功能的研究领域。首席研究员召集了一个 多学科指导委员会。他和他的导师概述了一个详细的深思熟虑的培训计划。 他将有80%的时间用于研究。范德比尔特提供了一个特殊的环境和强大的 机构承诺促进这名候选人向独立调查员过渡。