Platelets in Cardiovascular Biology and Pathology

心血管生物学和病理学中的血小板

• 批准号: 7878729
• 负责人: DENISA D WAGNER
• 金额: $ 69.36万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7878729
• 关键词: ADAMTS; Address; Adhesions; Adipose tissue; Affect; Animals; Apolipoprotein E; Arterial Fatty Streak; Atherogenic Diet; Atherosclerosis; Biology; Blood - brain barrier anatomy; Blood Circulation; Blood Platelets; Blood Vessels; Brain; Cardiovascular system; Cell Adhesion Molecules; Cessation of life; Coagulants; Coagulation Process; Collaborations; Cytoplasmic Granules; Defect; Deposition; Endothelium; Enzymes; Extravasation; Fibrin; Fibrosis; Functional disorder; Generations; Growth; H-Cadherin; Heart; Heart Diseases; Hemorrhage; Homeostasis; Implant; Inflammation; Inflammatory; Injury; Lesion; Leukocyte Rolling; Leukocytes; Ligands; Metalloproteases; Microcirculation; Microscopy; Modeling; Molecular; Molecular Analysis; Mus; Mutant Strains Mice; Operative Surgical Procedures; Organ; P-Selectin; Pathology; Patients; Permeability; Physiology; Plasma; Platelet Count measurement; Play; Role; Signal Transduction; TNFSF5 gene; Testing; Thrombin; Thrombosis; Thrombotic Thrombocytopenic Purpura; Thrombus; VWF gene; Vascular Permeabilities; Weibel-Palade Bodies; adhesion receptor; adiponectin; angiogenesis; base; in vivo Model; intravital microscopy; lipid mediator; matrigel; mouse model; plasma lead; prevent; programs; protective effect; sphingosine 1-phosphate

It is becoming evident that the importance of platelets in animal physiology far exceeds their role in vascular injury. In this proposal, we will address platelet function in angiogenesis, inflammation and heart disease. In addition, we will investigate the role of the metalloproteinase ADAMTS-13 and the effect of elevated procoagulant activity on vascular function, in particular in the brain. The project will be divided into three independent but thematically related Specific Aims. The first specific aim will develop our preliminary observations that platelets play an important role in angiogenesis by preventing hemorrhage. In collaboration with Project V (Hynes), we will test the hypothesis that platelet adhesion through adhesion receptors is required for angiogenesis. We will visualize platelet interactions with angiogenic vessels by multiphoton microscopy and study angiogenesis in mice mutant in various adhesion molecules. The role of platelet secretion in vessel stabilization will also be addressed. The second specific aim will study the pro-inflammatory functions of platelets and, with Project I (Krieger), the role of platelets in severe heart disease and atherosclerosis. We have observed that the presence of activated platelets in circulation, such as may occur in surgical patients, systemically activates endothelium and increases P-selectin expression. This is reflected in enhanced leukocyte rolling on the vessel wall. The molecular mechanisms of this new inflammatory platelet function will be explored. Knowing the role of platelets in inflammation, we were surprised to observe that in advanced heart disease, such as seen in the mouse models developed in Project I, platelet function had a protective effect on the animals. We hypothesize that platelets are crucial to prevent hemorrhage in the diseased heart, thus preventing excessive fibrosis of the organ. Fibrin deposition in the lesions was drastically reduced in the absence of platelets, indicating that platelets may be required for localized coagulation to occur. We will address this experimentally. The last aim will examine the consequences of pro-coagulant and pro-thrombotic conditions on blood vessel function. We have preliminary results that indicate that high levels of pro-coagulant microparticles in an animal's plasma lead to a breakdown of the endothelial blood-brain barrier. We hypothesize that this involves excessive thrombin generation/fibrin deposition resulting in signaling leading to vascular permeability. The proposed molecular mechanism will be studied. We have also begun analysis of mice lacking ADAMTS-13, a mouse model of thrombotic thrombocytopenic purpura (TTP). We will evaluate the role of this enzyme in platelet adhesion to endothelium and in thrombotic models. Project II will further collaborate with Project III (Lodish) on the role of adiponectin and T-cadherin in thrombosis and atherosclerosis.

越来越明显的是，血小板在动物生理学中的重要性远远超过其在血管中的作用。 受伤。在本提案中，我们将解决血管生成、炎症和心脏病中的血小板功能。在 此外，我们将研究金属蛋白酶 ADAMTS-13 的作用以及升高的促凝血剂的作用 对血管功能的活动，特别是对大脑的血管功能。该项目将分为三期 独立但主题相关的具体目标。 第一个具体目标将发展我们的初步观察结果，即血小板在 通过预防出血促进血管生成。与 Project V (Hynes) 合作，我们将检验假设 血小板通过粘附受体的粘附是血管生成所必需的。我们将可视化血小板 通过多光子显微镜与血管生成血管的相互作用并研究小鼠突变体的血管生成 各种粘附分子。还将讨论血小板分泌在血管稳定中的作用。 第二个具体目标是研究血小板的促炎功能，并且通过项目 I (Krieger)， 血小板在严重心脏病和动脉粥样硬化中的作用。我们观察到激活的存在 循环中的血小板（例如手术患者中可能出现的血小板）会系统性地激活内皮细胞并 增加 P-选择素表达。这反映在血管壁上的白细胞滚动增强。这 将探索这种新的炎症性血小板功能的分子机制。了解血小板的作用 在炎症中，我们惊讶地发现在晚期心脏病中，例如在小鼠中观察到的 在项目 I 开发的模型中，血小板功能对动物具有保护作用。我们假设 血小板对于防止患病心脏出血至关重要，从而防止心脏过度纤维化 器官。在没有血小板的情况下，病灶中的纤维蛋白沉积急剧减少，表明 发生局部凝血可能需要血小板。我们将通过实验解决这个问题。 最后一个目标是检查促凝血和促血栓形成条件对血管的影响 功能。我们的初步结果表明，高水平的促凝微粒 动物血浆会导致内皮血脑屏障的破坏。我们假设这涉及到 过度的凝血酶生成/纤维蛋白沉积导致信号传导导致血管通透性。这 将研究所提出的分子机制。我们还开始分析缺乏 ADAMTS-13 的小鼠，ADAMTS-13 是一种 血栓性血小板减少性紫癜（TTP）小鼠模型。我们将评估这种酶的作用 血小板粘附于内皮和血栓模型中。 项目 II 将与项目 III (Lodish) 进一步合作，研究脂联素和 T-钙粘蛋白在 血栓形成和动脉粥样硬化。