HDL Structure and its Function in Atherosclerosis

这个新项目的总体目标是对HDL生物学及其与动脉粥样硬化性心脏病的关系进行全面的结构、机制、功能和临床理解。该计划由3个重点和相互关联的项目组成，重点研究HDL病理生物学的各个方面，包括询问有关HDL颗粒发生，成熟，重塑，结构/功能，临床相关性以及在新型诊断和治疗干预中的应用的基本问题。每个项目还探讨了发生在动脉粥样硬化斑块内的特定氧化修饰对高密度脂蛋白结构和功能改变的潜在生物学后果。三个项目中提出的实验研究都依赖于与其他项目的协作互动。项目1探讨了HDL的新生和成熟形式的结构的基本问题，它与HDL成熟（LCAT）和胆固醇传递到肝脏和类固醇组织（SRB1）的蛋白质的复合物，以及人体血浆和动脉粥样硬化斑块中HDL的氧化修饰，这些修饰对颗粒的许多生物学功能产生不利影响。项目2探讨了各种参与者在动脉粥样硬化斑块消退的RCT过程中的作用，以及HDL和特定氧化形式的HDL在动脉粥样硬化斑块消退过程中调节巨噬细胞表型和血管壁内出口的作用。项目3研究了ABCA1在HDL生物发生过程中与apoA1相互作用的机制，对这一过程至关重要的特定结构特征，以及apoA1抗氧化形式作为促进动脉粥样硬化斑块消退的治疗方法的潜在用途。三个科学核心（质谱和生物物理、动脉粥样硬化回归、重组蛋白表达和分子克隆）和一个行政核心以经济有效的方式提供多项目支持、专业知识和服务，大大加强了整个研究计划。拟议的项目将进一步了解HDL和HDL相关蛋白复合物的结构特征，这些蛋白复合物对胆固醇稳态、逆向胆固醇转运和动脉粥样硬化斑块进展/退化至关重要。它还将确定在人类动脉粥样硬化中发生的位点特异性氧化修饰对HDL的功能和临床影响。最后，它还可能为心血管风险评估和治疗带来新的诊断和治疗方法。

The overall goals of this new Program Project are to develop a comprehensive structural, mechanistic, functional and clinical understanding of HDL biology and its relationship to atherosclerotic heart disease. The Program is comprised of 3 focused and interrelated Projects that focus on the common theme of investigating various aspects of HDL pathobiology, including asking fundamental questions about HDL particle genesis, maturation, remodeling, structure/function, clinical relevance and use in both novel diagnostic and therapeutic interventions. Each Project also explores the potential biological consequences of HDL alterations in structure and function by specific oxidative modifications that occur within atherosclerotic plaque. Experimental studies proposed in each of the three Projects rely upon collaborative interactions with each of the other Projects. Project 1 explores fundamental questions about the structure of nascent and mature forms of HDL, its complexes with proteins involved in HDL maturation (LCAT) and cholesterol delivery to the liver and steroidogenic tissues (SRB1), as well as oxidative modifications to HDL in human plasma and atherosclerotic plaque that adversely impact upon the many biological functions of the particle. Project 2 explores the role of various participants in the RCT processes in atherosclerotic plaque regression, and the role of both HDL, and specific oxidized forms of HDL, in modulating macrophage phenotype and egress within the vessel wall during atherosclerotic plaque regression. Project 3 studies mechanisms through which ABCA1 interacts with apoA1 during HDL biogenesis, specific structural features critical to this process, and the potential utility of oxidant resistant forms of apoA1 as a therapeutic for promoting atherosclerosis plaque regression. Three scientific cores (Mass Spectrometry and Biophysics; Regression of Atherosclerosis; and Recombinant Protein Expression and Molecular Cloning) and an Administrative Core provide multi-project support, expertise and service in a cost-effective manner, significantly strengthening the entire research program. The proposed Program Project will yield greater understanding of structural features of HDL and HDL-associated protein complexes critical to cholesterol homeostasis, reverse cholesterol transport, and atherosclerotic plaque progression/regression. It also will identify the functional and clinicai impact of site-specific oxidative modifications to HDL that occur within human atheroma. Finally, it may also lead to new diagnostic and therapeutic approaches toward cardiovascular risk assessment and therapy. The overall goals of this Program Project are to develop a comprehensive structural, mechanistic, functional and clinical understanding of HDL biology and its relationship to atherosclerotic heart disease. Each ofthe Projects explores both normal functions of HDL in cholesterol homeostasis and plaque regression, as well as in vivo functional consequences of HDL alterations in structure by specific oxidative modifications that occur within human atheroma. New diagnostic and therapeutic interventions are a major focus of investigation.