Structural and Cell Biology in Cardiovascular Disease

描述（由申请人提供）： 这个跨学科计划项目的总体主题是了解结构生物学，因此参与脂质进出细胞和身体不同器官之间运输的大分子和大分子复合物的结构-功能关系。脂质和特定蛋白质（载脂蛋白和其他脂质结合蛋白）的生物合成、组装和拆卸、相互转化、受体相互作用、辅因子和酶底物功能以及细胞摄取在脂质代谢的整体调节中起关键作用。 脂质和脂蛋白代谢中的生化缺陷在这些过程的不同水平上表达。这些缺陷导致血浆脂蛋白、细胞和细胞器膜以及细胞内脂质储存的组成、结构和物理性质的改变，这反过来可能导致疾病，如动脉粥样硬化、血栓形成、心肌缺血和糖尿病。Progam的总体目标包括研究脂蛋白、其组分载脂蛋白和脂蛋白受体以及其他细胞内和细胞外脂质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，四个高度相关的项目的研究将包括：（a）蛋白质和脂质组成以及环境条件对模型盘状HDL稳定性的影响，无脂质和贫脂质载脂蛋白中蛋白质-脂质相互作用的结构和动力学决定因素，以及LDL稳定性的关键分子决定因素。（项目1），（B）启动特异性脂质结合、组装和分泌所必需的apo B N末端的关键结构域，这些结构域和apo B合成共有序列的界面化学，以及正常和突变型apo B N末端结构域的结构。（项目2），（c）可交换载脂蛋白的构象和结构以及在脂质结合和盘状新生HDL转化为球形HDL时的构象变化，LDL和LDL上的apo-B的三维结构，LDL受体的配体结合结构域的结构，以及具有结合受体的LDL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转运（项目4）。 一个跨学科的方法，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，以及最先进的计算和结构生物学的方法被用来实现这些目标。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、脂肪酸诱导的缺血细胞损伤、糖尿病和动脉硬化。

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.