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.

项目摘要/摘要该提案中概述的研究将探索功能失调高密度的新型机制脂蛋白（HDL）会损害血小板功能并促进促血栓形成表型，并将测试创新减少动脉粥样硬化的潜在治疗策略。该建议是为了有指导的职业发展 Wenliang博士在医学系心血管医学系中获得奖范德比尔特大学。 Song博士的长期职业目标是成为独立资助的身体科学家专注于脂质代谢在心血管疾病中的作用。他已经在这个职业中投入了大量投资小路。他具有有关脂质过氧化和氧化应激，血小板生物学和啮齿动物的广泛研究背景心血管疾病的模型。最近的证据表明，HDL功能可能比 HDL胆固醇（HDL-C）。安装证据支持了功能失调的HDL的概念，例如氧化 HDL失去其有益特性，实际上有助于心血管疾病的发展。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为富含过氧化产物，包括丙二醛（MDA）和异甲列赛（Isolevuglandins）功能失调。新型的醛清道剂，靶向缓解反应性的不利影响氧化应激（ROS）而不废除ROS的正常信号，可以减少过氧化的修饰 HDL并防止形成功能失调的HDL。先前的研究表明，正常的HDL可以减少激动剂 - 刺激血小板激活和聚集，而氧化的HDL可增强血小板聚集，但机制尚不清楚。有趣的是，最近的研究表明，凋亡也发生在Anucleate中血小板和凋亡血小板在体内动脉血栓形成加速。众所周知，正常的HDL是在巨噬细胞和内皮细胞中，抗凋亡和氧化的HDL是促凋亡的，但从未研究过研究了HDL对血小板凋亡的影响。 Song博士假设功能失调的HDL，例如氧化来自FH患者（FH-HDL）的HDL和HDL，在体内增加血小板激活，从而增强血栓形成通过诱导的凋亡。 HDL和FH-HDL的过氧化修饰对血小板的影响凋亡和活性将进行测试。还将使用两个体内血栓形成小鼠模型（急性和慢性）。野生型，ldlr - / - 和apoa1 - / - ldlr - / - 小鼠将用于模仿FH条件，并评估 HDL的贡献。新颖的醛清除剂将用于保护HDL免受功能障碍并营救表型。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和推进动脉粥样硬化中HDL功能的领域。首席调查员已经组装了多学科指导委员会。他和他的导师概述了一个详尽的思想培训计划。他将有80％的受保护时间进行研究。范德比尔特（Vanderbilt）提供了一个特殊的环境和强大的环境机构承诺促进该候选人过渡到成为独立调查员的过渡。