血小板是一种从巨核细胞上衍生出的无核细胞质团，在血栓形成、炎症及宿主防御中具有重要的生理功能。血小板分泌功能的主要执行者是α-颗粒（AG）和δ-颗粒（DG），且均属于溶酶体相关细胞器，其生物发生或分泌缺陷，均会引起血小板功能异常。血小板分泌型颗粒的发生中，核心科学问题是不同颗粒的组成成分如何被精准的分选和运送，从而形成形态与功能迥异的AG和DG。我们前期研究发现，在与内吞体途径蛋白分选有关的BORC复合体（BLOC-one-related complex）的KXD1亚基缺失的Kxd1-KO突变体小鼠中，AG的分泌功能障碍，且回补ADP并不能恢复其分泌功能，提示KXD1可能参与AG的发生或者成熟，进而影响其分泌功能。本课题将从分子、细胞、超微结构三个层面阐明KXD1参与血小板AG发生和KXD1缺陷导致AG分泌功能障碍的分子细胞机制，为血小板AG的分选机制和相关疾病发生机制提供新的认识。

Platelet, a nonnucleated cytoplasmic mass derived from megakaryocytes, plays an important role in thrombosis, inflammation and host defence. Platelets contain two major types of secretory granules, α-granule (AG) and δ-granule (DG). Both AG and DG belong to lysosome-related organelles. Defects in the biogenesis or secretion of these granules lead to the dysfunction of platelet secretion. An intriguing question is how the constitutional components of AG and DG are sorted into these granules. BORC complex has been implicated in endosomal protein sorting. KXD1 is one subunit of BORC complex. Our preliminary data have shown that AG secretion was impaired in Kxd1-KO platelets, and ADP supplement could not restore the impairments, suggesting that KXD1 may play an important role in the biogenesis or maturation of platelet AG. In this proposal, we will elucidate the molecular mechanism of KXD1 in regulating the biogenesis or secretion of platelet AG at molecular, cellular and ultrastructural levels, to provide insights into sorting machinery of platelet AG and the pathogenesis of platelet disorders.