潘氏细胞大致密核心颗粒（LDCV）是一种溶酶体相关细胞器（LRO），其发生过程复杂，涉及到与多种细胞器互作。HPS综合征的病理特征是多种LRO的缺陷。HPS1患者表现有炎性肠病的发病机制不明。有报道HPS1小鼠突变体的黑素小体变大，其成熟过程需循环内体RE参与。我们前期工作表明，HPS1突变体小鼠潘氏细胞LDCV直径变大，其表型与黑素小体类似，暗示不同LRO的发生可能共享某些机制，即LDCV的成熟可能与RE有关，但尚未见报道。小肠隐窝蔗糖密度梯度离心结果显示，HPS1缺陷引起Rab38和VAMP7亚细胞分布改变。HPS1作为Rab38的GEF因子组分，其缺陷可能影响Rab38活性和亚细胞定位，进而影响LDCV成熟后期v-SNARE蛋白招募和通过RE的回收，导致LDCV成熟和分泌障碍。本项目将从物理接触和生理功能角度揭示LDCV与RE互作，并阐明互作分子机器，为炎性肠病发生和防治提供新思路。

Large dense core vesicle (LDCV) in Paneth cell is a type of lysosome-related oragnelles (LRO). Its biogenesis is complicated through interactions with various organelles. Hermansky-Pudlak syndrome (HPS) is characterized by multiple LRO defects. Many HPS1 patients present inflammatory bowel disease, but the pathogenesis is unknown. It has been reported that the melanosomes (a type of LRO) are enlarged in HPS1 mouse mutants, in which recycling endosomes (REs) are involved. Our unpublished data has shown that another type of LRO, LDCV in Paneth cell, exhibited enlargement in HPS1 mouse mutant, implicating a conserved mechanism in the maturation of LDCVs. That is, LDCV may interact with RE, which has no report yet. Our organelle distributional assays showed that HPS1 deficiency led to abnormal subcellular distribution of Rab38 and VAMP7. We proposed that the deficiency of HPS1, as a GEF component of Rab38, affects the activity and subcellular localization of Rab38. Abnormal Rab38 distribution affects the recruitment of v-SNARE proteins (such as VAMP7) and the interaction between LDCV and REs in late maturation stage of LDCVs, resulting in defective maturation and secretion of LDCVs. In this project, we will determine the interaction between LDCVs and REs from the perspective of physical contacts and functional relevance, and explore the molecular machinery that regulates the interaction between LDCVs and REs, to provide new insights into the pathogenesis and treatment of inflammatory bowel diseases.