HDL Structure and its Function in Atherosclerosis

这一新方案项目的总体目标是开发一个全面的结构，机械， HDL生物学的功能和临床理解及其与动脉粥样硬化性心脏病的关系。的 该计划由3个相互关联的项目组成，这些项目侧重于调查各种 HDL病理生物学方面，包括询问有关HDL颗粒发生的基本问题， 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。每个项目还探讨了HDL的潜在生物学后果 动脉粥样硬化内发生的特异性氧化修饰引起的结构和功能改变 斑块三个项目中提出的实验研究都依赖于与以下方面的合作互动： 每个其他项目。项目1提出的研究旨在提供新的见解， 高密度脂蛋白（HDL）的结构特征反过来有助于其正常的生物学功能 胆固醇转运，以及HDL apoA 1结构上不同位点特异性氧化修饰的作用 改变了人类脂蛋白的动脉粥样硬化保护功能。项目2探讨了各种 RCT过程中动脉粥样硬化斑块消退的参与者，以及HDL和 HDL的特定氧化形式，调节巨噬细胞表型和血管壁内的排出 在动脉粥样硬化斑块消退期间。项目3研究ABCA 1与 apoA 1在HDL生物合成过程中的作用，对该过程至关重要的特定结构特征，以及apoA 1的潜在用途。 抗氧化剂形式的apoA 1作为促进动脉粥样硬化斑块消退的治疗剂。三 科学核心（质谱和生物物理学;动脉粥样硬化的回归;和重组 蛋白质表达和分子克隆）和行政核心提供多项目支持， 以具有成本效益的方式提供专业知识和服务，大大加强了整个研究计划。的 拟议的计划项目将产生更好的理解HDL和HDL相关的具体结构特征 蛋白质复合物对胆固醇稳态、胆固醇逆向转运和 动脉粥样硬化斑块进展/消退。它还将确定特定部位的功能和临床影响， 氧化修饰HDL发生在人类动脉粥样硬化。最后，它还可能导致新的 心血管风险评估和治疗的诊断和治疗方法。

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 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 proposed studies aimed at providing new insights into how specific structural features of high density lipoprotein (HDL) contribute to its normal biological functions in reverse cholesterol transport, and the role of structurally distinct site-specific oxidative modifications to apoA1 of HDL in altered athero-protective functions of the lipoprotein in humans. 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 specific 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 clinical 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.