Secretion in Vascular Inflammation and Thrombosis

血管炎症和血栓形成中的分泌

• 批准号: 7278149
• 负责人: Guy L Reed
• 金额: $ 27.12万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-26 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7278149
• 关键词: Abbreviations; Acute; Affect; Alpha Granule; Apolipoprotein E; Arterial Fatty Streak; Arterial Injury; Arteries; Arteriosclerosis; Atherosclerosis; Blood; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cause of Death; Cytoplasmic Granules; Data; Defect; Development; Dissection; Enzymes; Event; Hermanski-Pudlak Syndrome; Human; Inflammatory; Injury; Lesion; Mediating; Molecular; Molecular Target; Mus; Myocardial Infarction; N-ethylmaleimide-sensitive protein; P-Selectin; Pathway interactions; Pharmaceutical Preparations; Platelet aggregation; Play; Process; Rab geranylgeranyltransferase; Rate; Role; Rupture; Stroke; TNFSF5 gene; Testing; Therapeutic; Thrombosis; Translating; Vascular remodeling; artery occlusion; cholesterol biosynthesis; in vivo; insight; mortality; novel; prevent; research study; therapeutic target; vascular inflammation

DESCRIPTION (provided by applicant): Despite recent improvements in mortality, cardiovascular diseases (heart attacks and strokes) remain the leading causes of death. Cardiovascular disease events are triggered by platelet aggregation. Beyond platelet aggregation, there is accumulating evidence that platelet secretion activates pro-thrombotic and pro-inflammatory pathways that cause acute thrombotic occlusion, mediate vascular remodeling and accelerate the atherosclerotic process. Unfortunately, there are no medications available to block the secretory process. Recently we and others have begun to elucidate the molecular mechanisms of platelet secretion. This proposal seeks to translate these molecular insights into experiments in vivo, that examine the novel hypothesis that platelet secretion could be a therapeutic target for preventing acute thrombotic arterial occlusion, arteriosclerotic vascular remodeling, atherosclerotic plaque rupture and the progression of atherosclerosis. We have selected two key molecular targets in the platelet secretory process. The first target is Rab geranylgeranyltransferase (RabGGTase), an enzyme downstream of the cholesterol biosynthesis pathway, which mediates the formation of platelet alpha granules that secrete pro-thrombotic and pro-inflammatory molecules (e.g., P-selectin, CD40L, etc.). The second target is HPS3p which plays an integral, selective role in the formation of platelet dense granules which contain ADP and other platelet activating molecules. Genetically altered mice deficient in RabGGTase or HPS3p will be used to determine how defects in alpha and/or dense granule secretion affect 1) the release of P-selectin, CD40L and other pro-inflammatory and pro-thrombotic molecules; 2) platelet aggregation; 3) thrombotic occlusion and vascular remodeling following acute vascular injury and, 4) the rates of plaque rupture and the progression of vascular lesions in ApoE-/- atherosclerotic mice. These experiments should define whether targeting these molecules to inhibit the platelet alpha and/or dense granule secretion could be an effective therapeutic strategy for reducing cardiovascular disease.

描述（由申请人提供）： 尽管死亡率最近有所改善，但心血管疾病（心脏病发作和中风）仍然是死亡的主要原因。心血管疾病事件是由血小板聚集触发的。除血小板聚集外，还有积累的证据表明，血小板分泌激活促脉症和促炎的途径，引起急性血栓闭塞，介导血管重塑并加速动脉粥样硬化过程。 不幸的是，没有可以阻止分泌过程的药物。 最近，我们和其他人开始阐明血小板分泌的分子机制。该提议旨在将这些分子见解转化为体内实验，该实验研究了新的假设，即血小板分泌可能是预防急性血栓性动脉闭塞，动脉粥样硬化血管性血管重塑，动脉粥样硬化斑块破裂和脑周期症的进展。我们在血小板分泌过程中选择了两个关键分子靶标。第一个靶标是Rab Geranylgeranylylansylysferase（Rabggtase），这是胆固醇生物合成途径下游的一种酶，它介导了血小板α颗粒的形成，该血小板颗粒的形成分泌了促促性性促性和促性分子和促性分子（E.G.，P-SELECTIN，CD40L等）。 第二个目标是HPS3P，它在包含ADP和其他血小板激活分子的血小板致密颗粒的形成中起着不可或缺的选择性作用。缺乏兔或HPS3P的遗传改变的小鼠将用于确定α和/或致密颗粒分泌的缺陷如何影响1）P-选择蛋白，CD40L和其他促炎和促炎和促疾病的分子的释放； 2）血小板聚集； 3）急性血管损伤后的血栓性闭塞和血管重塑，4）斑块破裂的发生率和APOE - / - 动脉粥样硬化小鼠中血管病变的进展。这些实验应定义靶向这些分子以抑制血小板α和/或致密颗粒分泌是否可能是减少心血管疾病的有效治疗策略。