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: 7450079
• 负责人: RAYMOND E BOISSY
• 金额: $ 16.67万
• 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 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7450079
• 关键词: Affect; Biogenesis; Cells; Chaperone Gene; Characteristics; Complex; Cytoplasm; Defect; Development; Functional disorder; Genes; Hereditary Disease; Hermanski-Pudlak Syndrome; Human; Localized; 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（由申请人提供）：皮肤色素沉着由黑化黑素体的合成调节。这些黑素体的生物发生是一个很好的模型，探索各种分子机制，管理伴侣的基因产物通过细胞质的不同位点的行动和/或细胞器。这些分子机制之一包括溶酶体相关细胞器复合物-2（BLOC-2）的生物发生，其在所有细胞类型中普遍表达。我们最近已经证明，在编码BLOC-2组件的基因突变的结果在Hermansky-Pudlak综合征（HPS）的皮肤色素脱失特征。我们建议测试的假设，即BLOC-2的功能，酪氨酸酶相关蛋白（TRP）的黑素体和突变的运输影响组件的复杂的与易位缺陷的TRP导致黑素合成效率低下的黑素体的HPS。这项研究将提供重要的见解，以了解细胞/分子机制，管理一般贩运和皮肤色素沉着的具体和铺平道路的发展，为Hermansky-Pudlak综合征的潜在治疗方法。项目叙述：人类遗传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中的合成位点转移到细胞中其他地方的功能位点。这项研究将集中在一个特定的伴侣复合物（BLOC- 2），交通黑素细胞特异性基因产物的黑素体细胞器作为一个模型，以了解所需的分子特性发生在所有细胞中的细胞贩运，并了解病理生理基础遗传疾病导致异常细胞贩运。