溶酶体相关细胞器参与血管稳态调节的机制

Lysosome-related organelles (LROs) are a family of specialized secretory organelles which share the conserved biosynthesis pathways of lysosomal trafficking. Platelet alpha- and delta-granules, endothelial Weibel-Palade bodies, dense vesicles in a variety of endocrine glands are members of LROs which undergo regulated secretion of molecules for regulating vascular homeostasis. However, the sorting mechanisms of these LROs during their biogenesis are largely unknown. It has been shown that several HPS (Hermansky-Pudlak syndrome) protein associated complexes (HPACs) such as AP-3, HOPS, BLOC-1/-2/-3 function in lysosomal trafficking and LRO biogenesis. Comparing the LRO defects of different mouse HPS mutants by using quantitative organelle proteomics and super-resolution microscopic analyses, we aim to dissect the underlying mechanisms in regulating the protein sorting into these LROs. Our ultimate goal is to understand the pathogenesis of bleeding, hypertension and atherosclerosis due to the defects of these specialized LROs.

溶酶体相关细胞器(lysosome-related organelle, LRO)是一类包括分泌型溶酶体在内的具有组织特异性并参与细胞分泌的细胞器，其发生和分泌过程与囊泡运输相关。血小板的致密颗粒、血管内皮细胞的Weibel-Palade小体、肾近球旁细胞的肾素颗粒均属于LRO，所分泌的物质参与血管的稳态维持与重构，称之为血管稳态相关LRO，其发生和分泌缺陷将引起相应组织细胞的功能障碍。LRO生物学(LRO biology)是近年来血管生物学新兴的重要研究领域。一些参与溶酶体运输的蛋白质复合体如BLOC-1/-2/-3，AP-3，HOPS等，参与LRO的发生。本研究将以这些溶酶体运输复合体缺陷的小鼠突变体为研究对象，利用定量细胞器蛋白质组学和高分辨显微成像等技术，研究它们在血管稳态相关LRO中的发生机制，阐明其缺陷所导致的血管稳态失调所引发的出血、高血压、动脉粥样硬化等疾病发生的病理机制。

本课题主要利用不同HPS小鼠突变体，揭示不同HPS基因所参与的HPS蛋白相关复合体（如BLOC-1/2/3, HOPS, AP-3等）在血管稳态相关LRO（主要为血小板致密颗粒、血管内皮细胞WPB小体、肾近球旁细胞肾素颗粒）中的分子细胞机制，并研究该发生过程障碍导致其释放异常的病理机制，以解析LRO的分泌缺陷导致血管稳态失调及其在出血、高血压和动脉粥样硬化中的作用。我们从影响血管稳态的溶酶体相关细胞器这一全新的角度，重点探讨存在于血小板、血管内皮细胞、肾脏近球旁细胞等组织特异性溶酶体相关细胞器的发生机制，发现了血小板致密体发生的关键蛋白TMEM163，重点阐明了H+对血管内皮细胞WPB小体发生的作用，以及发现HOPS复合体VPS33A亚基的突变影响肾素颗粒的发生和分泌。这些研究结果为理解高血压、高血脂、动脉粥样硬化、出凝血疾病等的发生机制提供了新视角。