III型PI3K-VPS34在血小板活化和血栓形成中的机制研究

磷酯酰肌醇-3激酶（PI3K）激酶是重要的细胞功能调控蛋白家族。该家族成员中的III型PI3K（VPS34）在血小板中的功能和机制未知。我们首先报道了III型PI3K在血小板中的表达，并发现体外抑制III型PI3K可以减弱血小板活化。为探索III型PI3K的体内作用，我们构建了血小板特异敲除III型PI3K的小鼠，发现该小鼠的病理性血栓形成受到抑制，但正常止血功能并未受影响，提示该分子可能是一个安全的新的抗血栓靶点。本课题在前期功能研究的基础上提出III型PI3K下游通过NOX活化、自噬、以及mTOR调控的细胞骨架重组的通路假说，拟通过基因敲除模型和分子生物学手段进行体内体外研究验证，最终明确III型PI3K在血小板中的信号通路机制。本课题将填补血小板领域内对III型PI3K研究的空白，加深对血小板精细调控机制的理解，发现并验证针对血栓性疾病的新的安全干预靶点。

Class III PI3K, also known as vacuolar protein sorting 34 (VPS34), is a member of PI3K family, which play important roles in diverse cellular functions. The role of class III PI3K in hemostasis and thrombosis is ill defined. With platelet specific VPS34 deficient mice, we have demonstrated that class III PI3K is vital in thrombosis, while dispensable in hemostasis. VPS34-/- platelets exhibited impaired activation in response to multiple agonists, which was phenocopied by using 3-methyladenine, a specific class III PI3K inhibitor in human platelets. These data indicate that class III PI3K might be a safe antiplatelet target. The present project aims to elucidate the signal transduction mechanism of platelet class III PI3K, with special emphasis on NADPH Oxidase activation pathway, autophagy pathway, and mTOR-regulated cytoskeleton reorgnization pathway. By unveiling the mechanism of class III PI3K VPS34, this project will strengthen the understanding of platelet activation process and thrombosis, and provide evidences for this molecule to be developed as a safe target in the better management of thrombotic diseases.