The composition and function of BLOC-2 in melanogenesis

BLOC-2在黑素生成中的组成和功能

• 批准号: 7618445
• 负责人: RAYMOND E BOISSY
• 金额: $ 20.05万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7618445
• 关键词: Affect; Biogenesis; Cells; Chaperone Gene; Characteristics; Complex; Cytoplasm; Defect; Development; Functional disorder; Genes; Hereditary Disease; Hermanski-Pudlak Syndrome; Human; Human Genetics; Lysosomes; Melanins; Melanogenesis; Melanosomes; Modeling; Molecular; Molecular Chaperones; Mutation; Organelles; Pathway interactions; Process; Property; Proteins; Research; Role; Site; Skin; Skin Pigmentation; Testing; Therapeutic; Tissues; Tyrosinase related protein-1; cell type; insight; melanocyte; trafficking

DESCRIPTION (provided by applicant): Skin pigmentation is regulated by the synthesis of melanized melanosomes. The biogenesis of these melanosomes is an excellent model to explore the various molecular mechanisms that govern the chaperoning of gene products through the cytoplasm to distinct sites of action and/or organelles. One of these molecular mechanisms includes the Biogenesis of Lysosome-related Organelle Complex-2 (BLOC-2), which is ubiquitously expressed within all cell types. We have recently demonstrated that mutations in the genes that encode BLOC-2 components results in skin depigmentation characteristic of Hermansky-Pudlak Syndrome (HPS). We propose to test the hypothesis that BLOC-2 functions in the trafficking of tyrosinase related proteins (TRPs) to the melanosome and mutations affecting components of this complex correlate with translocational defects of the TRPs resulting in inefficient melanin synthesis in the melanosomes of HPS. This research will provide important insights into the understanding of cellular/molecular mechanisms governing trafficking in general and skin pigmentation in specific and pave the way for the development of potential therapeutic treatments for Hermansky-Pudlak Syndrome. Project Narrative: A subset of human genetic disease results from the inability of the affected cell or tissue to get the required gene product from its site of synthesis in the cell to its site of function elsewhere in the cell. This research will focus on a specific chaperone complex (BLOC- 2) that traffics melanocyte specific gene products to the melanosome organelle as a model to understand the molecular properties required for cellular trafficking that occur in all cells and to understand the pathophysiology underlying genetic diseases resulting from aberrant cellular trafficking.

描述(申请人提供)：皮肤色素沉着由黑色素小体的合成来调节。这些黑素小体的生物发生是探索基因产物通过细胞质陪伴到不同作用部位和/或细胞器的各种分子机制的一个极好的模型。这些分子机制之一包括溶酶体相关的细胞器复合体-2(BLOC-2)的生物发生，它在所有类型的细胞中普遍表达。我们最近证实，编码BLOC-2组分的基因突变会导致Hermansky-Pudlak综合征(HPS)的皮肤脱色特征。我们建议检验这一假设，即BLOC-2在酪氨酸酶相关蛋白(TRPs)向黑素体的运输中发挥作用，并且影响该复合体成分的突变与TRP的移位缺陷有关，从而导致HPS黑素体中黑色素合成效率低下。这项研究将为了解控制一般运输和特定皮肤色素沉着的细胞/分子机制提供重要的见解，并为开发潜在的Hermansky-Pudlak综合征治疗方法铺平道路。项目简介：人类遗传性疾病的一个子集是由于受影响的细胞或组织无法将所需的基因产物从细胞内的合成部位转移到细胞内其他功能部位。这项研究将集中在一个特定的伴侣复合体(BLOC-2)，它将黑素细胞特定的基因产物运输到黑素小体细胞器作为模型，以了解在所有细胞中发生的细胞运输所需的分子性质，并了解由异常细胞运输导致的遗传病的病理生理学。