HDL Structure and its Function in Atherosclerosis

这个新的计划项目的总体目标是发展一个全面的结构，机制，功能和HDL生物学及其与动脉粥样硬化性心脏病的关系的临床理解。该计划由3个重点和相互关联的项目组成，重点关注调查HDL病理生物学各个方面的共同主题，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。每个项目还探讨了动脉粥样硬化斑块内发生的特定氧化修饰导致HDL结构和功能改变的潜在生物学后果。在这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探索了有关HDL的新生和成熟形式的结构的基本问题，其与HDL成熟（LCAT）和胆固醇递送到肝脏和类固醇生成组织（SRB 1）的蛋白质的复合物，以及对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RCT过程中各种参与者在动脉粥样硬化斑块消退中的作用，以及HDL和HDL的特定氧化形式在动脉粥样硬化斑块消退期间调节巨噬细胞表型和血管壁内的排出中的作用。项目3研究了ABCA 1在HDL生物合成过程中与apoA 1相互作用的机制，对该过程至关重要的特定结构特征，以及apoA 1抗氧化形式作为促进动脉粥样硬化斑块消退的治疗剂的潜在效用。三个科学核心（质谱和生物物理学;动脉粥样硬化的回归;重组蛋白表达和分子克隆）和一个行政核心以具有成本效益的方式提供多项目支持，专业知识和服务，显着加强整个研究计划。拟议的计划项目将产生更多的了解HDL和HDL相关蛋白复合物的结构特征，胆固醇稳态，胆固醇逆向转运和动脉粥样硬化斑块进展/消退的关键。它还将确定在人类动脉粥样硬化中发生的对HDL的位点特异性氧化修饰的功能和临床影响。最后，它也可能导致新的诊断和治疗方法，以心血管风险评估和治疗。 本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。每个项目都探讨了HDL在胆固醇稳态和斑块消退中的正常功能，以及HDL在人体动脉粥样硬化中发生的特定氧化修饰结构改变的体内功能后果。新的诊断和治疗干预措施是调查的主要焦点。

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.