Hermansky Pudlak Syndrome & melanosome formation

描述（由申请人提供）：Hermansky-Pudlak综合征（HPS）是一种遗传性多系统疾病，其中某些细胞类型中的组织特异性溶酶体相关亚细胞细胞器不正确形成。人类的6个基因和小鼠的另外10个基因中的任何一个发生突变都会导致HPS或HPS样综合征。对于大多数这些基因的产物，其功能是未知的。确定这些基因产物的功能作用是对抗这种疾病的关键。HPS的症状之一是眼皮肤白化病，这是由于黑色素小体、眼色素上皮中溶酶体相关细胞器以及皮肤和眼睛的黑色素细胞中黑色素的产生和储存的畸形引起的。黑素体的发育经历了一系列具有不同形态和特征的阶段，每个阶段都与人类色素细胞中与黑素体共存的传统内体和溶酶体不同。然而，黑素体和内体之间存在着密切的关系，因此需要复杂的、组织特异性的分选途径来分离运往不同舱室的货物。这种分选大部分发生在多泡室中。我们假设，负责分离货物的细胞机制包括在所有细胞类型中调节多泡内体分选的蛋白质以及hps相关基因的产物。我们进一步假设hps相关基因产物，特别是HPS3和block -1复合物的亚基，在功能上与更一般的内体因子相互作用，调节涉及黑素小体生物发生的组织特异性运输步骤。确定这些步骤将使我们了解独特的组织特异性细胞器是如何形成的，并将有助于开发针对HPS患者的治疗方法。具体目标是：

DESCRIPTION (provided by applicant): Hermansky-Pudlak Syndrome (HPS) is a heritable multisystem disorder in which tissue-specific, lysosome-related subcellular organelles in certain cell types are improperly formed. Mutations in any of 6 genes in humans and an additional 10 genes in mice cause HPS or an HPS-like syndrome. For the products of most of these genes, a function is not known. Defining the functional role of these gene products is a key to combating the disease. Among the symptoms of HPS is oculocutaneous albinism due to malformation of melanosomes, lysosome-related organelles in eye pigment epithelia and melanocytes of the skin and eye in which melanin pigments are made and stored. Melanosomes develop through a series of stages characterized by distinct morphologies and cargo, each of which are distinguishable from conventional endosomes and lysosomes that coexist with melanosomes in human pigment cells. Nevertheless, there is an intimate relationship between melanosomes and endosomes, such that complex, tissue-specific sorting pathways are required to segregate cargo destined for different compartments. Much of this sorting occurs in multivesicular compartments. We hypothesize that the cellular machinery responsible for segregating cargo includes proteins that regulate sorting at multivesicular endosomes in all cell types as well as the products of HPS-associated genes. We further hypothesize that the HPS-associated gene products, particularly HPS3 and subunits of the BLOC-1 complex, functionally interact with more general endosomal factors in regulating tissue-specific transport steps involved in melanosome biogenesis. Defining these steps will allow us to understand how unique tissue-specific organelles are formed and will help to develop therapies for HPS patients. The specific aims are: 1. To test the hypothesis that sorting of the stage I/II melanosome marker, Pmel17, relies on novel sorting determinants for sequestration within multivesicular endosomes. 2. To test the hypothesis that effectors of endosomal multivesicular body (MVB) formation regulate discrete stages of melanosome formation. 3. To test the hypothesis that HPS-associated gene products function in protein sorting at the stage I melanosome.