Platelets in Cardiovascular Biology and Pathology

心血管生物学和病理学中的血小板

• 批准号: 7515241
• 负责人: DENISA D WAGNER
• 金额: $ 50.65万
• 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/7515241
• 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; Condition; Cytoplasmic Granules; Defect; Deposition; Endothelium; Enzymes; Extravasation; Factor VIII-Related Antigen; Fibrin; Fibrosis; Functional disorder; Generations; Growth; H-Cadherin; Heart; Heart Diseases; Hemorrhage; Homeostasis; Implant; Inflammation; Inflammatory; Injury; Lesion; Leukocyte Rolling; Leukocytes; Ligands; Localized; Metalloproteases; Microcirculation; Microscopy; Modeling; Molecular; 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; von Willebrand Factor

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.

显而易见的是，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。在此提案中，我们将在血管生成，炎症和心脏病中解决血小板功能。在 此外，我们还将研究金属蛋白酶ADAMTS-13的作用以及升高的procogulant的作用 对血管功能的活性，尤其是在大脑中。该项目将分为三个 独立但主题相关的特定目的。 第一个具体目的将发展我们的初步观察，即血小板在 血管生成通过预防出血。与Project V（Hynes）合作，我们将检验该假设 血管生成需要通过粘附受体粘附。我们将可视化血小板 通过多光子显微镜和研究小鼠突变体的血管生成与血管生成血管的相互作用 各种粘附分子。血小板分泌在血管稳定中的作用也将得到解决。 第二个特定目的将研究血小板的促炎功能，并随着项目I（Krieger）， 血小板在严重心脏病和动脉粥样硬化中的作用。我们已经观察到存在激活 循环中的血小板，例如手术患者可能发生，系统地激活内皮和 增加P-选择素表达。这反映在血管壁上增强的白细胞滚动。这 将探索这种新的炎症血小板功能的分子机制。知道血小板的作用 在炎症中，我们惊讶地观察到在心脏病中，例如在小鼠中看到 在项目I I中开发的模型，血小板功能对动物具有保护作用。我们假设这一点 血小板对于预防患病心脏出血至关重要，从而防止过度纤维化 器官。在没有血小板的情况下，病变中的纤维蛋白沉积大大降低，表明 可能需要血小板才能发生局部凝血。我们将通过实验解决这个问题。 最后一个目标将检查促凝和亲凝结条件对血管的后果 功能。我们的初步结果表明，高水平的促凝微粒 动物的血浆导致内皮血脑屏障的崩溃。我们假设这涉及 过度凝血酶产生/纤维蛋白沉积导致信号传导导致血管渗透性。这 将研究提出的分子机制。我们还开始分析缺乏ADAMTS-13的小鼠，一个 血栓性血小板减少性紫癜（TTP）的小鼠模型。我们将评估该酶在 血小板粘附于内皮和血栓模型中。 II项目将进一步与项目III（Lodish）合作，讨论脂联素和T-辅助蛋白在 血栓形成和动脉粥样硬化。