Molecular Determinants of Pigmentation (MDoP)

色素沉着的分子决定因素 (MDoP)

• 批准号: 10204448
• 负责人: Zubair M. Ahmed
• 金额: $ 48.9万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10204448
• 关键词: Affect; Albinism; Alleles; Biochemical; Blindness; Candidate Disease Gene; Cells; Cellular biology; Childhood; Clinical; Communities; Counseling; Data; Detection; Development; Diagnosis; Disease; Embryo; Enrollment; Evaluation; Eye; Family; Family member; Gene Frequency; Gene Proteins; General Population; Genes; Genetic; Genetic Predisposition to Disease; Goals; Griscelli Syndrome; Hair; Hermanski-Pudlak Syndrome; Human; Impairment; Inherited; Iris; Knowledge; Link; Maintenance; Mammalian Cell; Maps; Melanins; Melanosomes; Minor; Mission; Modeling; Molecular; Molecular Diagnosis; Molecular Epidemiology; Mutate; Mutation; Mutation Detection; Neural Crest; Oculocutaneous Albinism; Optic Nerve; Pathogenicity; Pathologic Nystagmus; Pathology; Pattern; Phenotype; Photophobia; Pigmentation Disorders; Pigmentation physiologic function; Population Heterogeneity; Population Study; Prevalence; Prevention; Proteins; Psychophysics; Publishing; Reporting; Research; Role; Secondary Protein Structure; Skin; Structure; Structure of retinal pigment epithelium; Syndrome; TYR gene; TYRP1 gene; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Transportation; United States; United States National Institutes of Health; Variant; Vision Disorders; Visual impairment; Work; Zebrafish; base; clinical phenotype; clinical translation; clinically relevant; cohort; disability; exome sequencing; experience; gene function; genetic disorder diagnosis; genetic variant; genome editing; genome sequencing; genomic locus; improved; in silico; innovation; insight; melanoblast; melanocyte; new therapeutic target; novel; positional cloning; precision medicine; prediction algorithm; prevent; retinal rods; screening; spatiotemporal; stem; targeted treatment; therapeutic development; whole genome

“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.

“色素沉着的分子决定因素（mDoP）”研究旨在识别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）是儿童视力的主要原因之一。在美国，色素沉着障碍可表现为综合征，例如赫曼斯基-普德拉克综合征 (HPS)、格里塞利综合征 (GS) 和非综合症，例如眼皮肤白化病（OCA），在多种遗传模型下形成，目前，至少有十八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。 ，这强烈表明尚未发现其他基因，这使得科学界对色素沉着和色素障碍的构成和机制的完整了解存在空白。这项研究的长期目标是充分了解其机制。我们的假设是，如果突变基因导致色素沉着丧失，那么该基因的功能对于正常黑素细胞、黑色素合成和/或运输来说是必需的。拟议的 mDoP 研究的基本原理是，识别白化病的所有致病基因并了解其正常功能对于开发治疗这些损伤的治疗药物至关重要。因此，mDoP 研究与 NIH 的这部分使命相关。这涉及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，我们将通过识别和评估新的白化病基因来检验我们的假设。所提出的工作是创新的，因为它源于几个新的白化病基因座/基因的初步数据，这代表了已知基因的显着增加，并且它结合了当代技术mDoP 研究的发现和功能表征具有重要意义，因为所提出的研究的完成将为充分理解提供分子见解，并能够为有效治疗人类色素沉着和相关视力障碍提供目标。临床相关性，有可能改善色素沉着视觉疾病的分子流行病学，有助于遗传诊断、咨询和精准医疗。