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

基本信息

批准号：
8605068
负责人：
EDWARD Franklin PLOW
金额：
$ 38.47万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-15 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8605068
关键词：
Accounting Acute myocardial infarction Adhesions Area Arterial Fatty Streak Atherosclerosis Binding Biological Biological Markers Blood Blood Vessels Bone Marrow Transplantation CCL2 gene 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 Frequencies Genetic 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 Pathway interactions Patients Pattern Plasma Proteins Publishing Regulation Risk Factors Role Sampling Signal Pathway Signal Transduction Site Structure Testing Translating Variant Vascular System angiogenesis atherogenesis atherothrombosis base chemokine cytokine follow-up genetic variant in vivo in vivo Model insight macrophage member migration monocyte mouse model novel prognostic public health relevance receptor response thrombospondin 4 translational study vasa vasorum vascular inflammation

项目摘要

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（由适用提供）：对动脉粥样硬化病变的发展至关重要的是血液和血管细胞与细胞外基质（ECM）成分之间的相互作用。该提案重点介绍了ECM蛋白质蛋白质蛋白质蛋白-4（TSP-4）的作用。我们发表的研究和初步数据强烈暗示了TSP-4在血管壁中的炎症调节中，因此，在TSP-4 KO小鼠中，动脉粥样硬化被明显抑制。在TSP-4 KO小鼠中，机械学降低了多个白细胞粘附分子和单核细胞趋化蛋白（MCP-1）的表达，而在TSP-4 KO小鼠中的表达很少导致巨噬细胞（M€）积累到发育中的病变中，从而抑制了动脉粥样硬化中的关键事件。此外，在TSP-4 KO小鼠中抑制了动脉粥样硬化的另一种EC反应，这是TSP-4 KO小鼠的血管生成，这是TSP-4是促血管生成的第一个证据。在这些新颖的观察结果上叠加的是我们的发现（现在在众多独立的研究中复制），高频遗传变异p387 tsp-4与A387形成对比，是动脉粥样硬化的风险因素。要测试的主要假设是，TSP-4激活了调节细胞基质动力学和血管感染的血管细胞中的特定分子机制和途径，并且p387变体凸显了这些促动脉粥样硬化反应，包括血管生成。表达P387 TSP-4变体的新型敲入小鼠将允许在体内检验该假设。提出了三个具体目的：1）使用TSP-4 KO和p387 TSP-4 K-IN小鼠定义TSP-4变体在动脉粥样硬化中的作用，并与原位杂交结合进行骨髓移植，以确定动脉粥样硬化中的差异是否取决于血液和/或血管细胞。 2）确定使用TSP-4 KO和p387 TSP-4 K-IN小鼠的TSP-4在体内TSP-4的差异反应的分子机制。 3）。进行翻译研究以确定人类冠状动脉的病变和非仪化区域中TSP-4的关系，动脉粥样硬化和血管生成。我们发现了一个新的等离子体生物标志物TSP-4RA，在一小部分AMI患者面板中显着升高。将遵循此铅来确定AMI患者的TSP-4RA是否有选择地升高，对于第二AMI的预后，并且在患者中达到的水平上会影响细胞反应。我们的总体目标是确定TSP-4在血管细胞生物学中的作用，确定其促进质和预后功能的分子机制，并确定小鼠和人类研究中p387 TSP-4变体是否增强了这些功能。