Impact of Dysfunctional HDL on Platelet Function and in vivo Thrombosis

项目摘要/摘要 该提案中概述的研究将探索新的机制，通过这些机制，功能失调的高密度 脂蛋白(HDL)会损害血小板功能，促进血栓前表型，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。这项建议是为了一个有指导的职业发展 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内科科学家 重点阐述了脂代谢在心血管疾病中的作用。他已经在这一职业生涯中投入了大量资金 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，高密度脂蛋白功能可能是一个比 高密度脂蛋白(高密度脂蛋白胆固醇)。越来越多的证据支持这一概念，例如，功能失调的高密度脂蛋白被氧化 高密度脂蛋白，失去了有益的特性，实际上导致了心血管疾病的发展。 这项建议中的初步数据表明，家族性高胆固醇血症(FH)患者的高密度脂蛋白 富含过氧化产物，包括丙二醛(MDA)和异uglandins(IsoLG)，以及 令人震惊的功能失调。新型醛清除剂，有针对性地减轻活性物质的不良影响 氧化应激(ROS)在不破坏ROS正常信号的情况下，可以减少细胞的过氧化修饰 降低高密度脂蛋白，防止形成功能失调的高密度脂蛋白。先前的研究表明，正常的高密度脂蛋白可以减少激动剂- 刺激血小板活化和聚集，而氧化的高密度脂蛋白增强血小板聚集，但 机制尚不清楚。有趣的是，最近的研究表明，细胞凋亡也发生在无核细胞中。 血小板，以及凋亡的血小板加速体内动脉血栓的形成。众所周知，正常的高密度脂蛋白是 抗凋亡和氧化的高密度脂蛋白在巨噬细胞和内皮细胞中是促凋亡的，但还没有研究 探讨高密度脂蛋白对血小板凋亡的影响。宋博士假设，功能失调的高密度脂蛋白，如氧化 高密度脂蛋白和FH患者高密度脂蛋白(FH-HDL)，体内增加血小板活化导致血栓形成 通过诱导细胞凋亡。高密度脂蛋白和FH-高密度脂蛋白过氧化修饰对血小板的影响 将检测细胞的凋亡率和活性。还将使用两种体内血栓形成小鼠模型(急性和慢性)。 野生型LDLR-/-和ApoA1-/-LDLR-/-小鼠将被用来模拟FH条件，并评估 高密度脂蛋白的贡献。新型乙醛清除剂将用于保护高密度脂蛋白免受功能障碍和拯救 表型。这项拟议的研究将为高密度脂蛋白对血小板生物学和 推进高密度脂蛋白在动脉粥样硬化血栓形成中的作用。首席调查员已经召集了一支 多学科指导委员会。他和他的导师概述了一份详细的深思熟虑的训练计划。 他将有80%的受保护时间用于研究。范德比尔特提供了一个特殊的环境和强大的 机构承诺，以促进这位候选人向独立调查员的过渡。

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.