Molecular Determinants of Pigmentation (MDoP)

“色素沉着的分子决定因素（mDoP）”研究旨在鉴定和表征人类色素沉着发育、黑素体运输、功能和维持所必需的新基因和蛋白质。色素沉着障碍（通常称为白化病）是美国儿童视力障碍的主要原因之一。色素沉着障碍可以表现为综合征，如Hermansky-Pudlak综合征（HPS）、Griscelli综合征（GS）和非综合征，如OCA，在多种遗传模式下形成。目前，至少有18个基因座的突变与人类白化病有因果关系。然而，已知的基因并不能解释这些疾病的所有病例，这强烈表明其他基因尚未被发现，这在科学界对色素沉着和色素紊乱的构成和机制的全面理解上留下了空白。本研究的长期目标是充分了解遗传性色素沉着障碍的机制，并开发治疗和预防白化病的药物。我们的假设是，如果一个突变基因导致色素沉着丧失，那么该基因的功能将是正常黑色素细胞、黑色素合成和/或运输所必需的。提出mDoP研究的基本原理是，确定白化病的所有致病基因并了解其正常功能将是开发治疗这些损伤的治疗药物的关键。因此，mDoP研究与NIH的使命有关，即发展可能有助于减轻人类残疾负担的基础知识。在强有力的初步数据的指导下，我们将通过鉴定和评估新的白化病基因来检验我们的假设。拟议的mDoP研究将采用当代人类和斑马鱼的遗传、分子、生化、心理物理和细胞生物学技术。拟议的工作具有创新性，因为它源于几个新的白化病基因位点/基因的初步数据，这些数据代表了已知基因的显着增加，并且它结合了当代技术来识别和功能表征新的白化病基因。mDoP研究意义重大，因为拟议研究的完成将提供分子见解，以充分了解并能够为有效治疗人类色素沉着和相关视力障碍提供靶点。mDoP的研究结果具有重要的临床意义，对改善色素视力障碍的分子流行病学、基因诊断、心理咨询和精准医疗具有潜在的指导意义。

“Molecular Determinants of Pigmentation (mDoP)” study aims to identify and characterize new genes and proteins essential for pigmentation development, melanosomes transportation, function and maintenance in humans. Pigmentation disorders (often referred as albinism) represents one of the major causes of childhood vision impairment in United States. Pigmentation disorders can manifest in syndromic, e.g., Hermansky-Pudlak syndrome (HPS), Griscelli syndrome (GS) and nonsyndromic, e.g., Oculocutaneous albinism (OCA), forms under a variety of inheritance models. At present, mutations in at least eighteen loci have been causally linked with albinism in humans. However, the known genes do not account for all cases of these disorders, which strongly suggests that other genes have yet to be found, leaving a gap in the scientific community’s complete understanding of the makeup and mechanisms of pigmentation and pigmentary disorders. The long-term goal of this research is to fully understand the mechanisms of inherited pigmentation disorders and to develop therapeutic agents for the treatment and prevention of albinism. Our hypothesis is that if a mutated gene causes loss of pigmentation, then the function of that gene will be necessary for normal melanocytes, melanin synthesis and/or transportation. The rationale for the proposed mDoP study is that identifying all causative genes for albinism and understanding their normal function will be pivotal for the development of therapeutic agents to treat these impairments. Thus, mDoP study is relevant to that part of NIH’s mission that pertains to developing fundamental knowledge that will potentially help to reduce the burdens of human disability. Guided by strong preliminary data, we will test our hypothesis through identification and evaluation of novel albinism genes. The proposed mDoP studies will employ contemporary human and zebrafish genetic, molecular, biochemical, psychophysical and cell biology techniques. The proposed work is innovative, as it stems from preliminary data of several new albinism loci/genes, which represent a significant increase from the known genes, as well as it uses combination of contemporary technologies to identify and functionally characterize novel albinism genes. The mDoP study is significant because the completion of the proposed research will provide molecular insights to fully understanding and being able to provide targets for effectively treat pigmentation and related vision disorders in humans. Results of mDoP study hold great clinical relevance, with the potential to improve the molecular epidemiology of pigmentation-vision disorders, aid in genetic diagnosis, counseling and precision medicine.