Pigmentation-dependent melanosomal disease

描述（由申请人提供）：黑色素小体是一种专门的黑色素细胞细胞器，其存在是为了执行高度专业化的任务，产生和储存黑色素。黑色素作为一种保护剂抵御紫外线辐射的破坏性影响。因此，人体皮肤中黑色素的存在通常是促进健康的关键因素。不幸的是，黑素体也与潜在的致病因素有关。关键问题是，许多黑色素合成的中间体是高活性的醌类，能够引起显著的氧化损伤。与色素生成相关的异常氧化应激与几种皮肤疾病，包括皮肤自身免疫性疾病和恶性黑色素瘤有关。尽管具有这种重要性，但对黑素体含有或解毒这些化合物的能力有贡献的生物过程和超微结构成分在很大程度上是未知的。在这里，我们提出了初步的实验，鉴定了一种新的黑素体蛋白GPNMB，我们假设它参与了黑素体含有或解毒黑色素合成中潜在的细胞毒性中间体的能力。我们将利用现有的Gpnmb突变小鼠菌株和利用扫描透射x射线显微镜的基于同步加速器的成像技术的遗传上位实验的组合来测试我们的假设。这些实验的完成将确定GPNMB蛋白在皮肤黑素体中的功能，并开始阐明该蛋白在健康和色素沉着疾病中的作用。黑素小体是黑素细胞的一种特殊细胞器，在健康时产生和储存黑色素，在疾病中导致各种与黑素细胞有关的皮肤疾病。本研究的目的是利用遗传和创新成像方法的结合，启动新发现的黑素体蛋白GPNMB的功能测试。这些研究的完成将在GPNMB的黑素体功能方面取得重要进展，并创造促进这一研究领域发展所需的资源。

DESCRIPTION (provided by applicant): Melanosomes are a specialized organelle of melanocytes that exist in order to conduct a highly specialized task, producing and storing melanin pigment. Melanin acts as a protective agent against the damaging effects of UV radiation. Thus, the presence of melanin in human skin normally contributes to a key element promoting health. Unfortunately, melanosomes are also associated with disease causing potential. Of key concern, many of the intermediates of melanin synthesis are highly reactive quinones and capable of causing significant oxidative damage. Aberrant oxidative stress associated with pigment production has specifically been implicated in several skin diseases, including cutaneous autoimmune disease and malignant melanoma. Despite this importance, the biological processes and ultrastructural components contributing to the ability of melanosomes to contain or detoxify these compounds are largely unknown. Here, we present our preliminary experiments identifying a new melanosomal protein, GPNMB, which we hypothesize participates in the ability of melanosomes to contain or detoxify the potentially cytotoxic intermediates of melanin synthesis. We will test our hypothesis using a combination of genetic epistasis experiments that take advantage of existing Gpnmb mutant mouse strains and synchrotron based imaging techniques that utilize scanning transmission X-ray microscopy. Completion of these experiments will identify a function of the GPNMB protein in melanosomes of the skin, and begin to clarify the role of this protein in health and diseases of pigmentation. Melanosomes are a specialized organelle of melanocytes that in health produce and store melanin pigment and in disease contribute to a variety of skin diseases involving melanocytes. The goal of this research is to initiate functional tests of the newly identified melanosomal protein, GPNMB, utilizing a combination of genetic and innovative imaging approaches. Completion of these studies will yield important gains concerning the melanosomal functions of GPNMB and create needed resources that will facilitate growth of this area of research.