The mutational mechanisms shaping melanocytes in human skin

塑造人类皮肤黑素细胞的突变机制

• 批准号: 10581888
• 负责人: Alan Hunter Shain
• 金额: $ 42.67万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-17 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581888
• 关键词: Address; Affect; Aging; Anatomy; Area; Automobile Driving; Back; Base Pairing; Biological; Biological Assay; Cancer Etiology; Cataloging; Catalogs; Cell division; Cells; Chronic; Communities; Complement; Complex; DNA Damage; DNA Repair; DNA sequencing; Data; Etiology; Evolution; Exposure to; Face; Genes; Genome; Genomics; Genotype; Goals; Grant; Guide prevention; Guidelines; Head and neck structure; Human; Human body; In Vitro; Incidence; Individual; Knowledge; Laboratories; Malignant Neoplasms; Measures; Methods; Molecular; Mutagens; Mutation; Normal tissue morphology; Observational Study; Observational epidemiology; Occupational Exposure; Organ; Pattern; Periodicals; Persons; Pigments; Prevention; Prevention strategy; Process; Public Health; Radiation Induced DNA Damage; Recording of previous events; Recreation; Reporting; Research; Research Personnel; Resolution; Risk; Risk Factors; Role; Sensitivity and Specificity; Shapes; Shoulder; Site; Skin; Skin Cancer; Somatic Mutation; Sun Exposure; Sunbathing; Testing; UV Radiation Exposure; UV induced; Ultraviolet Rays; cancer genomics; cancer risk; course development; epidemiology study; expectation; experience; innovative technologies; insight; melanocyte; melanoma; preneoplastic cell; prevent; repaired; the sun; tissue/cell culture; tumor; ultraviolet irradiation

Project Summary/Abstract As a barrier organ, skin forms the main defense against ultraviolet (UV) radiation, a potent mutagen emitted by the sun. The mutational damage incurred through this role can lead to melanoma, the deadliest form of skin cancer. Contrary to expectations, melanoma is more common on body sites that are only exposed to UV radiation intermittently, such as the back and shoulder, rather than body sites exposed more continuously, such as the head/neck areas. We recently reported the first catalogue of somatic mutations in melanocytes from normal human skin and discovered that melanocytes from the back/trunk had higher mutation burdens than donor-matched melanocytes from the head/neck areas. Based on our mutational observations and the anatomic patterns of melanoma, we hypothesize that melanocytes on the head/neck areas have evolved mechanisms to accumulate mutations more slowly than melanocytes from other body sites – likely an adaptation to counterbalance the higher levels of cumulative sun exposure affecting those sites. If true, this would alter prevention strategies. Moreover, a better understanding of the mechanisms by which melanocytes accumulate mutations would reveal molecular strategies to slow down this process and reduce the incidence of melanoma. We will test our hypothesis in aim 1 by comparing somatic mutations in melanocytes of different anatomic origins within-people and in aim 2 by cataloguing somatic mutations in site-matched melanocytes across people who offer detailed histories of sun exposure. These studies will offer correlative data implicating the main factors driving up the mutation burdens in melanocytes. A major obstacle to these studies is that it is difficult to measure somatic mutations in individual cells at a high degree of accuracy. However, we recently pioneered a workflow to call mutations in individual melanocytes at nearly 100% specificity and sensitivity. To complement these observational studies, in aim 3, we will measure in vitro the rates at which melanocytes of different anatomic origins repair DNA damage and dissect the main mechanisms regulating this process. Towards this goal, we have developed assays to measure UV-radiation-induced DNA damage at single base- pair resolution in tissue-cultured cells. Taken together, the scientific approaches employed in this proposal are technologically innovative and will illuminate the mutational mechanisms operating on melanocytes in normal human skin, addressing major gaps in knowledge that have vexed the skin research community.

项目总结/文摘