Secretion in Vascular Inflammation and Thrombosis

描述（由申请人提供）： 尽管最近死亡率有所改善，但心血管疾病（心脏病发作和中风）仍然是死亡的主要原因。心血管疾病事件由血小板聚集触发。除了血小板聚集，越来越多的证据表明，血小板分泌激活促血栓形成和促炎途径，导致急性血栓闭塞，介导血管重塑和加速动脉粥样硬化过程。 不幸的是，没有药物可以阻止分泌过程。 最近，我们和其他人已经开始阐明血小板分泌的分子机制。该提案旨在将这些分子见解转化为体内实验，研究血小板分泌可能是预防急性血栓性动脉闭塞，动脉粥样硬化血管重塑，动脉粥样硬化斑块破裂和动脉粥样硬化进展的治疗靶点的新假设。我们选择了血小板分泌过程中的两个关键分子靶点。第一个靶标是Rab香叶基香叶基转移酶（RabGGT酶），其是胆固醇生物合成途径下游的酶，其介导血小板α颗粒的形成，所述血小板α颗粒分泌促血栓形成和促炎分子（例如，P-选择素、CD 40 L等）。 第二个靶点是HPS 3 p，它在含有ADP和其他血小板活化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。RabGGT酶或HPS 3 p缺陷的遗传改变的小鼠将用于确定α和/或致密颗粒分泌缺陷如何影响1）P-选择素、CD 40 L和其它促炎和促血栓形成分子的释放; 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）ApoE-/-动脉粥样硬化小鼠斑块破裂率和血管病变进展。这些实验应该确定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。

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.