Role of BLOC-3 in Lysosome and Melanosome Biogenesis

BLOC-3 在溶酶体和黑素体生物发生中的作用

• 批准号: 6779917
• 负责人: ESTEBAN C DELL'ANGELICA
• 金额: $ 30.39万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6779917
• 关键词: albinism; cell component structure /function; electron microscopy; eye disorder; fibroblasts; fluorescence microscopy; genetic disorder; intracellular transport; laboratory mouse; lysosomes; melanocyte; melanosomes; microtubule associated protein; protein localization; protein protein interaction; tissue /cell culture

DESCRIPTION (provided by applicant): Melanosomes are cell-type-specific, membrane-bounded organelles in which melanin pigments are synthesized and stored. Abnormalities in melanosome biogenesis seem to underlie the pigmentation defects and visual problems associated with several human genetic disorders, such as X-linked ocular albinism 1 (OA1) and various types of Hermansky-Pudlak syndrome (HPS). Unlike OA1, all characterized types of HPS display additional clinical manifestations not related to melanosome function (e.g., prolonged bleeding), and are due to mutations in genes that are expressed ubiquitously. This has led to the idea that the products of HPS genes are involved in the biogenesis of several types of related organelles, including melanosomes, platelet dense granules and lysosomes. The goal of this project is to elucidate the function(s) of the products of the HPS1 and HPS4 genes, which are associated with two severe forms of HPS. Preliminary studies in our laboratory have revealed that HPS1 and HPS4 are components of a stable protein complex, termed Biogenesis of Lysosome-related Organelles Complex-3 (BLOC-3), which in fibroblasts is required for normal intracellular distribution of lysosomal-associated membrane proteins. The plan consists of three specific aims: (1) to determine the function of BLOC-3 in cells that contain lysosomes but lack specialized organelles such as melanosomes; (2) to determine the function of BLOC-3 in melanosome biogenesis, using primary melanocyte cultures from control and HPS1- or HPS4-mutant mice; and (3) to establish the mechanism(s) of action of BLOC-3 at the molecular level. This research may provide important insights into the basic question of how melanosomes and related organelles are formed, and pave the way for the development of potential treatments for HPS.

描述（由申请人提供）：黑色素体是细胞型特异性的，结合膜结合的细胞器，合成和储存黑色素色素。黑色素体生物发生异常似乎是与几种人遗传疾病相关的色素沉着缺陷和视觉问题的基础，例如X连锁的眼白化病1（OA1）和各种类型的Hermansky-Pudlak综合征（HPS）。与OA1不同，所有特征性的HP类型都显示出与黑色素体功能无关的额外临床表现（例如，长时间出血），并且是由于普遍表达的基因突变所致。这导致了这样的想法，即HPS基因的产物参与了几种类型的相关细胞器的生物发生，包括黑素体，血小板致密颗粒和溶酶体。 该项目的目的是阐明HPS1和HPS4基因产物的功能，这些功能与两种严重的HPS相关。在我们实验室中的初步研究表明，HPS1和HPS4是稳定的蛋白质复合物的组成部分，称为溶酶体相关细胞器复合物的生物发生复合物（BLOC-3），在成纤维细胞中是正常细胞内溶酶体与溶酶体相关膜膜蛋白的细胞内分布所必需的。该计划由三个特定目的组成：（1）确定包含溶酶体但缺乏专门细胞器（例如黑素体）的细胞中BLOC-3的功能； （2）使用对照和HPS1或HPS4突变小鼠的原代黑素细胞培养物来确定Bloc-3在黑色素体生物发生中的功能； （3）在分子水平上建立bloc-3的作用机理。这项研究可能会为如何形成黑素体和相关细胞器的基本问题提供重要的见解，并为开发HP的潜在治疗方法铺平道路。