Biogenesis of HDL Through Cholesterol Efflux and ApoA-I Structural Reorganization

HDL 通过胆固醇流出和 ApoA-I 结构重组的生物合成

• 批准号: 8874470
• 负责人: Mary G Sorci-Thomas
• 金额: $ 54.72万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874470
• 关键词: 3-Dimensional; ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Address; Affect; Animal Model; Apolipoprotein A-I; Applications Grants; Atherosclerosis; Biogenesis; Cardiovascular Diseases; Catabolism; Cell membrane; Cells; Cessation of life; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Chronic; Cysteine; Development; Disease; Enhancers; Equilibrium; Extracellular Matrix; Functional disorder; Goals; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Immune; In Vitro; Infection; Inflammatory; Intracellular translocation; Knowledge; Laboratories; Lipid Binding; Lipids; Liver; Maintenance; Malignant Neoplasms; Maps; Measures; Mediating; Membrane Microdomains; Metabolism; Molecular; Molecular Conformation; Morbidity - disease rate; Movement; Mus; Myocardial Infarction; Pathway interactions; Phospholipids; Plasma; Play; Process; Proteins; Publishing; Recombinants; Reporter; Role; Side; Signal Transduction; Source; Sphingomyelins; Tissues; Trauma; United States; base; combat; cost; insight; intermolecular interaction; macrophage; mortality; mouse model; mutant; novel; particle; prevent; procollagen C-endopeptidase; protein protein interaction; public health relevance; reverse cholesterol transport

 DESCRIPTION (provided by applicant): The overall goal of this grant proposal entitled "Biogenesis of HDL Through Cholesterol Efflux and ApoA-I Structural Reorganization" is to define a novel role for Procollagen C Proteinase Enhancer 2 (PCPE2) in the formation and function of HDL as it relates to the progression of atherosclerosis. By 2025, worldwide death due to atherosclerosis and associated complications is projected to surpass that of every major disease, including cancer, infection and trauma. The total cost of atherosclerosis-related diseases in the U.S. alone is estimated to be $286 billion annually. After statins, there is no break-through strategy in the pipeline to combat this deadly global disease. Our laboratory has studied the role of HDL apoA-I in atherosclerosis for the last 25 years and have shown, as others have, that apoA-I is an important modulator of atherosclerosis. Despite this clarity, all attempts to reduce atherosclerosis in humans by pharmacologically raising HDL levels have failed. Many believe this is a result of increasing plasma HDL concentrations without increasing or raising its "functionality". Therefore, we expect to show that PCPE2 enhances HDL functionality at both the level of cholesterol efflux, as well as, its role in HDL turnover and catabolism. To do this we have crafted three specific aims. Specific Aim 1: To investigate molecular transitions of specific apoA-I helical domains responsible for promoting the biogenesis of nascent HDL (nHDL). Specific Aim 2: Delineate the role of the accessory protein, PCPE2 in nHDL assembly by examining interactions between these two proteins and to determine how this interaction affects the opening of lipid-free apoA-I. Specific Aim 3. Examine the role PCPE2 plays in mediating HDL metabolism and in the development of atherosclerosis in a newly created LDLr- /-, PCPE2-/- mouse model. At the end of the project, we expect that PCPE2 will be found to be a novel molecule mechanistically involved in increasing HDL functionality in humans providing a new strategy for combating atherosclerosis.

 描述（由申请人提供）：这项题为“通过胆固醇外排和ApoA-I结构重组生物发生HDL”的资助提案的总体目标是确定前胶原蛋白C蛋白酶增强剂2（PCPE 2）在HDL形成和功能中的新作用，因为它与动脉粥样硬化的进展有关。到2025年，全世界因动脉粥样硬化和相关并发症造成的死亡预计将超过每一种主要疾病，包括癌症、感染和创伤。仅在美国，动脉粥样硬化相关疾病的总成本估计为每年2860亿美元。在他汀类药物之后，没有突破性的战略可以对抗这种致命的全球性疾病。我们实验室在过去的25年里研究了HDL apoA-I在动脉粥样硬化中的作用，并与其他实验室一样，证明apoA-I是动脉粥样硬化的重要调节剂。尽管如此，所有试图通过提高HDL水平来减少人类动脉粥样硬化的尝试都失败了。许多人认为这是增加血浆HDL浓度而不增加或提高其“功能性”的结果。因此，我们期望表明PCPE 2在胆固醇流出水平以及其在HDL周转和catalysts中的作用上增强HDL功能。为此，我们制定了三个具体目标。具体目标1：目的：研究促进新生HDL（nHDL）生物合成的apoA-I螺旋结构域的分子转变。具体目标二：通过检查这两种蛋白质之间的相互作用来描述辅助蛋白PCPE 2在nHDL组装中的作用，并确定这种相互作用如何影响无脂质apoA-I的开放。具体目标3。在新创建的LDLr- /-，PCPE 2-/-小鼠模型中检查PCPE 2在介导HDL代谢和动脉粥样硬化发展中的作用。在该项目结束时，我们预计PCPE 2将被发现是一种新的分子，在机制上参与增加人类HDL功能，为对抗动脉粥样硬化提供新的策略。