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：
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
项目类别：
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

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（由申请人提供）：动脉粥样硬化病变发展的关键是血液和血管细胞与细胞外基质 (ECM) 成分之间的相互作用。本提案重点关注 ECM 蛋白血小板反应蛋白-4 (TSP-4) 的作用。我们发表的研究和初步数据强烈表明 TSP-4 可以调节血管壁炎症，因此，TSP-4 KO 中动脉粥样硬化得到显着抑制。 TSP-4 KO 小鼠内皮细胞 (EC) 机械性地降低了多种白细胞粘附分子和单核细胞趋化蛋白 (MCP-1) 的表达，导致少量巨噬细胞 (M�) 积聚到正在形成的病变中，从而抑制了体内的关键事件。此外，在动脉粥样硬化形成中重要的另一种 EC 反应——血管生成，在 TSP-4 KO 小鼠中受到抑制，这是 TSP-4 是一种动脉粥样硬化形成的第一个证据。与这些新的观察结果相叠加的是我们的发现（现已在许多独立研究中得到重复），即与 A387 相比，高频遗传变异 P387 TSP-4 是动脉粥样硬化血栓形成的危险因素。 TSP-4 激活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，并且 P387 变体增强了这些促动脉粥样硬化反应，包括血管生成。表达 P387 TSP-4 变体的新敲入小鼠将允许在体内测试这一假设：1) 使用 TSP-4 KO 和 P387 TSP-4 定义 TSP-4 变体在动脉粥样硬化中的作用。 K-In 小鼠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) 确定差异反应背后的分子机制。使用 TSP-4 KO 和 P387 TSP-4 K-In 小鼠对 TSP-4 变体进行 EC 分析并表征 TSP-4 的体内促血管生成活性 3)。我们发现了一种新的血浆生物标志物 TSP-4RA，该标志物在一小部分 AMI 患者中显着升高。确定 TSP-4RA 在 AMI 患者中是否选择性升高，是否可预测第二次 AMI，并且在患者中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，确定其促动脉粥样硬化和促血管生成功能的分子机制，并确定在小鼠和人类研究中 P387 TSP-4 变体是否增强了这些功能。