TSP-4 genetic variants in atherogenesis and angiogenesis

动脉粥样硬化和血管生成中的 TSP-4 遗传变异

• 批准号: 9204851
• 负责人: EDWARD Franklin PLOW
• 金额: $ 39.25万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204851
• 关键词: Acute myocardial infarction; Adhesions; Area; Arterial Fatty Streak; Atherosclerosis; Binding; Biological; Biological Markers; Blood; Blood Vessels; Bone Marrow Transplantation; Carotid Artery Ulcerating Plaque; Cause of Death; Cell Communication; Cell physiology; Cells; Cellular biology; Complex; Coronary artery; Data; Development; Disease; Endothelial Cells; Event; Extracellular Matrix; Extracellular Matrix Proteins; Family; Follow-Up Studies; Frequencies; Genetic study; Goals; Heart; Human; In Situ Hybridization; In Vitro; Inflammation; Inflammatory; Integrins; Knock-in Mouse; Knock-out; Knockout Mice; Lead; Lesion; Leukocyte Adhesion Molecules; Leukocyte-Adhesion Receptors; Ligands; Molecular; Monocyte Chemoattractant Proteins; Mus; Myocardial Infarction; Pathogenicity; Pathway interactions; Patients; Pattern; Plasma; Proteins; Publishing; Recruitment Activity; Regulation; Risk Factors; Role; Sampling; Signal Pathway; Signal Transduction; Site; Structure; Testing; Thrombospondins; Translating; Variant; Vascular System; angiogenesis; atherogenesis; atherothrombosis; chemokine; cytokine; genetic variant; in vivo; in vivo Model; insight; macrophage; member; migration; monocyte; mouse model; novel; predictive marker; prognostic; public health relevance; receptor; response; thrombospondin 4; translational study; vasa vasorum; vascular inflammation

DESCRIPTION (provided by applicant): Critical to the development of atherosclerotic lesions is the interaction between blood and vascular cells with components of the extracellular matrix (ECM). This proposal focuses on the role of an ECM protein, thrombospondin-4 (TSP-4). Our published studies and preliminary data strongly implicate TSP-4 in regulation of inflammation in the vessel wall, and, as a consequence, atherosclerosis is markedly suppressed in the TSP- 4 KO mouse. Mechanistically reduced expression of multiple leukocyte adhesion molecules and monocyte chemotactic protein (MCP-1) by endothelial cells (EC) in TSP-4 KO mice leads to few macrophages (M�) accumulating into developing lesions, thereby suppressing a key event in atherogenesis. Furthermore, another EC response important in atherogenesis, angiogenesis, is suppressed in TSP-4 KO mice, the first evidence that TSP-4 is a pro-angiogeneic. Superimposed on these novel observations is our finding (now replicated in numerous independent studies) that a high frequency genetic variant, P387 TSP-4 as contrasted to A387, is an atherothrombotic risk factor. The primary hypothesis to be tested is that TSP-4 activates specific molecular mechanisms and pathways in vascular cells that regulate cell-matrix dynamics and vascular inflammation and that the P387 variant accentuates these pro-atherogenetic responses, including angiogenesis. A new knock-in mouse expressing P387 TSP-4 variant will permit testing this hypothesis in vivo. Three specific aims are proposed: 1) To define the role of the TSP-4 variants in atherosclerosis using TSP-4 KO and P387 TSP-4 K-In mice and to perform bone marrow transplantation in combination with in situ hybridization to determine if differences in atherosclerosis are dependent on blood and/or vascular cells. 2) To identify the molecular mechanisms underlying the differential responses of EC to the TSP-4 variants and characterize the proangiogenic activity of TSP-4 in vivo using TSP-4 KO and P387 TSP-4 K-In mice. 3). To perform translational studies to determine relationships between TSP-4, atherogenesis and angiogenesis in lesioned and non-lesioned areas of human coronary arteries. We found a new plasma biomarker, TSP-4RA, that was markedly elevated in a small panel of AMI patients. This lead will be followed to determine if TSP-4RA is selectively elevated in AMI patients, is prognostic for second AMI, and, at levels attained in patients, influences cellular responses. Our overall goals are to establish the roles of TSP-4 in vascular cell biology, to identify the molecular mechanisms underlying its proatherogenic and proangiogenic functions, and to determine whether these functions are enhanced by the P387 TSP-4 variant in mouse and human studies.

描述（由申请人提供）：血液和血管细胞与细胞外基质（ECM）组分之间的相互作用是动脉粥样硬化病变发展的关键。该建议侧重于ECM蛋白血栓反应蛋白-4 （TSP-4）的作用。我们发表的研究和初步数据强烈暗示TSP-4参与血管壁炎症的调节，因此，TSP-4 KO小鼠的动脉粥样硬化明显受到抑制。在TSP-4 KO小鼠中，内皮细胞（EC）的多种白细胞粘附分子和单核细胞趋化蛋白（MCP-1）的表达机制降低，导致少量巨噬细胞(M)积聚形成病变，从而抑制动脉粥样硬化的一个关键事件。此外，另一种在动脉粥样硬化中重要的EC反应，血管生成，在TSP-4 KO小鼠中被抑制，这是TSP-4是促血管生成的第一个证据。在这些新的观察结果的基础上，我们发现（现在在许多独立研究中得到了重复），与A387相比，高频遗传变异P387 TSP-4是一种动脉粥样硬化血栓形成的危险因素。需要验证的主要假设是，TSP-4激活了血管细胞中调节细胞基质动力学和血管炎症的特定分子机制和途径，而P387变体强化了这些促动脉粥样硬化反应，包括血管生成。一种新的表达P387 TSP-4变体的敲入小鼠将允许在体内验证这一假设。提出了三个具体目标：1)利用TSP-4 KO和P387 TSP-4 K-In小鼠确定TSP-4变异在动脉粥样硬化中的作用，并结合原位杂交进行骨髓移植，以确定动脉粥样硬化的差异是否依赖于血液和/或血管细胞。2)利用TSP-4 KO和P387 TSP-4 K-In小鼠，研究EC对TSP-4变异差异反应的分子机制，并在体内表征TSP-4的促血管生成活性。3)。开展转化性研究，以确定人类冠状动脉病变区和非病变区TSP-4与动脉粥样硬化和血管生成之间的关系。我们发现了一种新的血浆生物标志物，TSP-4RA，在一小组AMI患者中显著升高。将根据这一线索确定AMI患者中TSP-4RA是否选择性升高，是否对第二次AMI的预后有影响，以及患者达到的水平是否会影响细胞反应。我们的总体目标是确定TSP-4在血管细胞生物学中的作用，