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)仍然是主要的死亡原因。心血管疾病事件是由血小板聚集引发的。除了血小板聚集，越来越多的证据表明，血小板分泌激活了血栓前和促炎途径，导致急性血栓闭塞，介导血管重塑，加速动脉粥样硬化过程。不幸的是，目前还没有药物可以阻断这种分泌过程。 最近，我们和其他人开始阐明血小板分泌的分子机制。这项提议旨在将这些分子洞察力转化为体内实验，以检验血小板分泌可作为预防急性血栓闭塞、动脉硬化性血管重塑、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。第一个靶点是Rab geranylgeranyl转移酶(RabGGTase)，这是胆固醇生物合成途径下游的一种酶，它介导血小板α颗粒的形成，分泌促血栓和促炎分子(如P-选择素、CD40L等)。第二个靶点是HPS3p，它在血小板致密颗粒的形成中起着完整的、选择性的作用，其中含有ADP和其他血小板激活分子。缺乏RabGGTase或HPS3p的转基因小鼠将被用来确定阿尔法和/或致密颗粒分泌缺陷如何影响1)P-选择素、CD40L和其他促炎和促血栓分子的释放；2)血小板聚集；3)急性血管损伤后血栓闭塞和血管重塑；4)ApoE-/-动脉粥样硬化小鼠斑块破裂和血管病变的进展。这些实验应该确定以这些分子为靶点抑制血小板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.