炎性肠病（IBD）是一种受遗传因素和环境因素共同影响的严重免疫性疾病，IBD患者小肠α-防御素的表达量显著下降。α-防御素由小肠独有的细胞亚群潘氏细胞（PC）分泌，是小肠免疫的重要因子，可调控肠道共生微生物平衡，其减少将导致肠道对外来病原菌的敏感性增加。PC的分泌功能主要由一种溶酶体相关细胞器（LRO）--大致密核心颗粒(LDCV)所司职。已报道编码不同LRO生物发生复合体(BLOC)亚基的基因如HPS1、4和6的突变可导致HPS(Hermansky-Pudlak综合征)相关IBD，并可能伴随防御素的分泌减少。但它们所参与组成的BLOC复合体在PC分泌防御素的作用机制目前并不清楚。我们的初步结果表明BLOC-2缺陷的ru (Hps6)小鼠中小肠防御素的稳态水平下降约1/3。本研究将利用ru小鼠为模型，研究BLOC-2在潘氏细胞LDCV发生和分泌中的作用，以揭示HPS相关IBD的发生机制。

Inflammatory bowel disease (IBD) is a severe immune disorder that influenced by both genetic and environmental factors. Patients with IBD show reduced intestinal α-defensin expression which compromises antibacterial defense of the hosts. Paneth cell, the major source of α-defensin in small intestine, is a unique group of secretory cell featured with large dense core vesicles, which are lysosome-related organelles. Mutations of Hermansky-Pudlak syndrome (HPS) genes HPS1, HPS4 and HPS6, which encode subunits of Biogenesis of Lysosome-related Organelles Complexes (BLOCs), lead to HPS-IBD characterized by reduced Paneth cell α-defensin level. However, the underlying mechanism of how BLOCs regulate Paneth cell secretion is largely unknown. Our preliminary data showed that the intestinal steady-state level of α-defensin was decreased about one-third in BLOC-2 mutant mice. In this study, we focus on the function of HPS6 (a subunit of BLOC-2) in regulating the biogenesis and secretion of LDCV in Paneth cell. Uncovering this underlying mechanism will provide insights into the innate immune mechanism in small intestine and new clues to the treatment of IBD.