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: 7269855
• 负责人: ESTEBAN C DELL'ANGELICA
• 金额: $ 29.65万
• 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 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7269855
• 关键词: Address; Angelica; Antibodies; Binding; Biogenesis; Blood Platelets; Cell Fractionation; Cell physiology; Cells; Clinical; Color; Compatible; Complex; Cytoplasmic Granules; Defect; Development; Dynein ATPase; Electron Microscopy; Eye Development; Family member; Fibroblasts; Fluorescence Microscopy; Generations; Genes; Glues; Goals; Hemorrhage; Hereditary Disease; Hermanski-Pudlak Syndrome; Human; Integral Membrane Protein; Intracellular Membranes; Laboratories; Link; Lysosomes; Melanins; Melanosomes; Membrane; Membrane Proteins; Microscopy; Microtubules; Molecular; Motor; Mus; Mutant Strains Mice; Mutation; Ocular Albinism; Organelles; Pathologic Nystagmus; Phospholipids; Pigmentation physiologic function; Pigments; Platelet Storage Pool Deficiency; Protein Overexpression; Proteins; Pulmonary Fibrosis; Research; Research Personnel; Role; Skin; System; Testing; Time; Visual; Visual Acuity; base; cell motility; cell type; dynactin; insight; melanocyte; novel; programs; research study; segregation; trafficking; tyrosine kinase ABL1

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）：黑素体是细胞类型特异性的、膜结合的细胞器，黑色素在其中合成和储存。黑素体生物发生的异常似乎是与多种人类遗传性疾病相关的色素沉着缺陷和视觉问题的基础，例如 X 连锁眼部白化病 1 (OA1) 和各种类型的赫曼斯基-普德拉克综合征 (HPS)。与 OA1 不同，所有特征类型的 HPS 都表现出与黑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。这导致人们认为 HPS 基因的产物参与几种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。 该项目的目标是阐明 HPS1 和 HPS4 基因产物的功能，这些基因与两种严重的 HPS 形式相关。我们实验室的初步研究表明，HPS1 和 HPS4 是一种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-3 (BLOC-3) 的生物发生，在成纤维细胞中，该复合物是溶酶体相关膜蛋白在细胞内正常分布所必需的。该计划包括三个具体目标：（1）确定BLOC-3在含有溶酶体但缺乏特化细胞器（如黑素体）的细胞中的功能； (2) 使用对照小鼠和 HPS1 或 HPS4 突变小鼠的原代黑素细胞培养物确定 BLOC-3 在黑素体生物发生中的功能； (3) 在分子水平上建立BLOC-3的作用机制。这项研究可能为黑素体和相关细胞器如何形成的基本问题提供重要的见解，并为开发 HPS 的潜在治疗方法铺平道路。