HPS6在大致密核心颗粒发生过程中的作用及机制

大致密核心颗粒（large dense-core vesicles，LDCVs）是溶酶体相关细胞器（lysosome-related organelles，LROs）的一种，受到刺激时快速释放活性多肽，调节机体生长发育、行为发展以及生理平衡和稳定。LDCV生物学发生的调控机制及调节型分泌蛋白的胞质分选机器目前并不明确。HPS6是溶酶体相关细胞器生物发生复合体-2的一个亚基，参与调控溶酶体和多种细胞特异性LROs的生物学发生，我们的前期工作发现HPS6缺陷的细胞中调节型分泌蛋白含量明显减少，且LDCV单个颗粒的分泌动力学明显改变，据此我们提出HPS6可能作为新的调控分子，介导LDCV发生过程中货物的分选和招募，进而调控LDCV的形成和功能。我们将首先分析HPS6缺陷小鼠嗜铬细胞中LDCV的分子组成、亚细胞结构及分泌功能变化，然后重点阐明HPS6调节LDCV发生的分子细胞机制。

Polypeptides play central roles in development, behavior, and physiology. The regulated release of them depends on their inclusion within large dense-core vesicles (LDCVs). LDCVs are characterized as a class of lysosome-related organelles (LROs)，but the mechanism governing the biogenesis of them and the cytosolic machinery involved in this regulated secretory pathway (RSP) have remained poorly understood. HPS6 is a subunit of lysosome-related organelles complex-2 (BLOC-2) which is involved in the endolysosomal pathway and in the formation of LROs. Our preliminary results show that loss of HPS6 reduces the cellular content of the RSP protein, dysregulates the kinetics of single vesicle exocytosis. We hypothesize that HPS6 is likely a new regulator in the recruitment of the RSP proteins and in the biogenesis of LDCVs. In this study, we aim to evaluate the role of HPS6 in the sorting machinery during the formation of LDCV, to define the morphological and functional changes of LDCVs in HPS6 defective cells, and to explore the possible molecular and cellular mechanisms.