Platelets in Cardiovascular Biology and Pathology

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它们在血管中的作用。 受伤。在这项提案中，我们将讨论血小板在血管生成、炎症和心脏病中的作用。在……里面 此外，我们将研究金属蛋白酶ADAMTS-13的作用以及升高的促凝剂的作用 对血管功能的活动，特别是在大脑中。该项目将分为三个部分 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，即血小板在 通过防止出血来促进血管生成。在项目V(Hynes)的协作下，我们将检验这一假设 血小板通过黏附受体的黏附是血管生成所必需的。我们将把血小板形象化 多光子显微镜观察血管与新生血管的相互作用及基因突变小鼠血管生成的研究 各种黏附分子。此外，还将讨论血小板分泌在血管稳定中的作用。 第二个具体目标将研究血小板的促炎功能，并在项目I(Krieger)中， 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，被激活的 循环中的血小板，如可能发生在外科患者中，系统性地激活内皮细胞和 增加P-选择素的表达。这反映在增强的白细胞在血管壁上滚动。这个 这种新的炎性血小板功能的分子机制将被探索。了解血小板的作用 在炎症方面，我们惊讶地发现，在晚期心脏病中，就像在老鼠身上看到的那样 在项目I中开发的模型中，血小板功能对动物具有保护作用。我们假设 血小板对防止心脏出血至关重要，从而防止心脏过度纤维化。 管风琴。在没有血小板的情况下，病变中的纤维蛋白沉积显著减少，这表明 局部凝血可能需要血小板。我们将通过实验来解决这个问题。 最后一个目标是检查促凝血剂和促血栓形成条件对血管的影响。 功能。我们有初步结果表明，高水平的促凝剂微粒在 动物的血浆导致血管内皮细胞血脑屏障的破坏。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转导导致血管通透性。这个 提出的分子机制将被研究。我们还开始分析缺乏ADAMTS-13的小鼠，A 血栓性血小板减少性紫癜(TTP)小鼠模型。我们将评估这种酶在 在血栓形成模型中，血小板与内皮细胞的黏附。 项目II将进一步与项目III(Loish)就脂联素和T-钙粘素在 血栓形成和动脉粥样硬化。

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.