The composition and function of BLOC-2 in melanogenesis

描述（由申请人提供）：皮肤色素沉着由黑素小体的合成调节。这些黑素体的生物发生是探索基因产物通过细胞质到达不同作用位点和/或细胞器的各种分子机制的一个很好的模型。其中一个分子机制包括溶酶体相关细胞器复合物-2 （block -2）的生物发生，它在所有细胞类型中普遍表达。我们最近已经证明编码block -2成分的基因突变导致Hermansky-Pudlak综合征（HPS）特征的皮肤色素沉着。我们提出验证block -2在酪氨酸酶相关蛋白（TRPs）运输到黑素小体中的功能，并且影响该复合物组分的突变与TRPs易位缺陷相关，导致HPS黑素小体中黑色素合成效率低下。这项研究将为理解控制贩运的一般细胞/分子机制和特定的皮肤色素沉着提供重要的见解，并为开发Hermansky-Pudlak综合征的潜在治疗方法铺平道路。项目说明：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从细胞内的合成位点获得所需的基因产物到细胞内其他部位的功能位点。本研究将重点关注一种特定的伴侣复合物（BLOC- 2），该复合物将黑素细胞特异性基因产物运输到黑素小体细胞器，作为一种模型，以了解发生在所有细胞中的细胞运输所需的分子特性，并了解由异常细胞运输引起的遗传疾病的病理生理学基础。

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.