Pigmentation-dependent melanosomal disease

描述(申请人提供)：黑素小体是黑素细胞的一个专门细胞器，它的存在是为了执行高度专业化的任务，生产和储存黑色素。黑色素作为一种保护剂，可以抵御紫外线辐射的破坏作用。因此，人类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，黑素小体也与致病潜力有关。值得关注的是，黑色素合成的许多中间体都是高度活性的苯二酚，能够引起显著的氧化损伤。与色素产生相关的异常氧化应激特别与几种皮肤病有关，包括皮肤自身免疫性疾病和恶性黑色素瘤。尽管这很重要，但对黑素小体抑制或解毒这些化合物的能力起作用的生物学过程和超微结构成分在很大程度上是未知的。在这里，我们介绍了我们的初步实验，确定了一种新的黑素体蛋白，GPNMB，我们假设它参与了黑素小体包含或解毒黑色素合成的潜在细胞毒性中间体的能力。我们将结合利用现有的GPNMB突变小鼠品系的遗传上位性实验和利用扫描透射式X射线显微镜的基于同步辐射的成像技术来验证我们的假设。这些实验的完成将确定GPNMB蛋白在皮肤黑素小体中的功能，并开始阐明这种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个特殊细胞器，在健康情况下产生和储存黑色素，在疾病中导致涉及黑素细胞的各种皮肤病。这项研究的目标是利用遗传和创新成像方法的组合，启动对新发现的黑素体蛋白GPNMB的功能测试。这些研究的完成将产生关于GPNMB黑素体功能的重要成果，并创造必要的资源，促进这一研究领域的发展。

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.