Structural and Cell Biology in Cardiovascular Disease

描述(由申请人提供)： 这个跨学科项目的总体主题是了解大分子和大分子复合体的结构生物学，从而了解大分子和大分子复合体的结构-功能关系，这些大分子和大分子复合体涉及脂质进出细胞和身体不同器官之间的运输。生物合成、组装和分解、相互转化、受体相互作用、辅因子和酶底物功能以及细胞对脂类和特定蛋白质(载脂蛋白和其他脂类结合蛋白)的摄取在脂类代谢的整体调控中起着关键作用。脂类和脂蛋白代谢中的生化缺陷在这些过程的不同水平上表现出来。这些缺陷会导致血浆脂蛋白、细胞膜和细胞器膜以及细胞内脂肪储存的组成、结构和物理性质的改变，进而可能导致动脉粥样硬化、血栓形成、心肌缺血和糖尿病等疾病。PROGAM的总体目标包括研究脂蛋白、其组成的载脂蛋白、脂蛋白受体以及其他细胞内外脂结合蛋白的生物发生、构象、三维结构、稳定性和相互转化。为了实现这些总体目标，四个高度相互关联的项目的研究将包括：(A)蛋白质和脂肪组成和环境条件对模型盘状高密度脂蛋白稳定性的影响，无脂和贫脂载脂蛋白中蛋白质-脂相互作用的结构和动力学决定因素，以及低密度脂蛋白稳定性的关键分子决定因素。(项目1)，(B)apoB N端启动特定脂结合、组装和分泌所需的临界域，这些结构域的界面化学和apoB的合成共识序列，以及正常和突变apoB的N端域的结构。(项目2)，(C)可交换载脂蛋白的构象和结构以及脂结合和盘状新生高密度脂蛋白转化为球形高密度脂蛋白时的构象变化，低密度脂蛋白和载脂蛋白B在低密度脂蛋白上的三维结构，低密度脂蛋白受体的配体结合域的结构，以及低密度脂蛋白与受体结合的结构。(D)脂肪酸与脂肪酸结合蛋白的分子相互作用、胞质脂肪酸结合蛋白的结构和动力学以及与配体的相互作用，以及脂肪酸在模型膜和细胞中的运输(项目4)。为了实现这些目标，使用了一种跨学科的方法，其中包括蛋白质和脂质生物化学和生物物理学、分子和细胞生物学以及最新的计算和结构生物学方法。这些信息将允许开发新的基于分子的策略来控制血脂异常、脂肪酸在缺血、糖尿病和动脉硬化中引起的细胞损伤。

DESCRIPTION (provided by applicant): The overall theme of this interdisciplinary Program Project is to understand the structural biology and hence structure-function relationships of the macromolecules and macromolecular complexes involved in the transport of lipids into and out of cells and between different organs of the body. The biosynthesis, assembly and disassembly, inter-conversions, receptor interactions, cofactor and enzyme substrate functions, and cellular uptake of lipids and specific proteins (apolipoproteins and other lipid-binding proteins) play key roles in the overall regulation of lipid metabolism. Biochemical defects in lipid and lipoprotein metabolism express themselves at different levels of these processes. These defects lead to alterations in the composition, structure and physical properties of the plasma lipoproteins, cellular and organelle membranes, and intracellular lipid stores that in turn may contribute to diseases such as atherosclerosis, thrombosis, myocardial ischemia, and diabetes. The overall objectives of the Progam include studies of the biogenesis, conformation, three-dimensional structure, stability, and interconversion of lipoproteins, their constituent apolipoproteins, and lipoprotein receptors together with other intra- and extra-cellular lipid binding proteins. To achieve these overall objectives, studies in the four highly inter-related projects will encompass: (a) The effects of protein and lipid composition and environmental conditions on the stability of model discoidal HDL, the structural and kinetic determinants of protein-lipid interactions in lipid-free and lipid-poor apolipoproteins, and the key molecular determinants of LDL stability. (Project 1), (b) Critical domains in the N terminal of apoB necessary to initiate specific lipid-binding, assembly and secretion, the interfacial chemistry of these domains and synthetic consensus sequences of apoB, and the structure of the N terminal domains of normal and mutant apoB. (Project 2), (c) The conformation and structure of exchangeable apolipoproteins and the conformational changes on lipid binding and as discoidal nascent HDL is converted to spherical HDL, the three-dimensional structure of LDL and apo-B on LDL, the structure of the ligand binding domain of the LDL receptor, and the structure of LDL with bound receptor. (Project 3), and (d)The molecular interactions of fatty acids with fatty acid binding proteins, the structures and dynamics of cytosolic fatty acid binding proteins and interactions with ligands, and the transport of fatty acids in model membranes and cells (Project 4). An interdisciplinary approach that encompasses protein and lipid biochemistry and biophysics, molecular and cell biology, and state-of-the-art methods of computational and structural biology is used to obtain these objectives. Such information will allow the development of new molecular-based strategies to control dyslipoproteinemias, fatty acid-induced cellular damage in ischemia, diabetes and arteriosclerosis.