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Mechanisms of UV-Mediated Melanoma Development

紫外线介导的黑色素瘤发展机制

基本信息

批准号：
10616760
负责人：
Christin E Burd
金额：
$ 34.23万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-04 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10616760
关键词：
Acceleration Alleles BRAF gene Biological Biological Process Cell Line Cells Cutaneous Melanoma DNA DNA Repair DNA Sequence Alteration DNA lesion Data Data Set Development Disease Disease Progression Dose Etiology Exposure to Gene Mutation Genetic Genetic Transcription Genetically Engineered Mouse Genome Genomics Genotoxic Stress Growth Human Immunotherapeutic agent Incidence Individual Intervention Knowledge Mediating Melanins Melanoma Cell Metabolic Modeling Mus Mutagenesis Mutant Strains Mice Mutation Neonatal Neoplasm Metastasis Newborn Animals Nucleotide Excision Repair Oncogenes Oxidation-Reduction Pathology Pathway interactions Patient-Focused Outcomes Pattern Physiological Physiological Processes Pigmentation physiologic function Pigments Prevention strategy Production Prognosis Recording of previous events Relative Risks Research Residual state Risk Risk Factors Role Site Skin Skin Pigmentation Sun Exposure Sunburn Sunlight Sunscreening Agents System Testing Transcription-Coupled Repair UV Mutagenesis UV Radiation Exposure UV carcinogenesis UV protection UV response Ultraviolet B Radiation Ultraviolet Rays Work combat exome sequencing experimental study human disease immune cell infiltrate improved in vivo irradiation melanocyte melanoma mutant mutant mouse model pheomelanin repaired response the sun transcriptome sequencing transcriptomics tumor tumor growth tumor microenvironment tumorigenesis tumorigenic ultraviolet ultraviolet damage ultraviolet lesions

项目摘要

ABSTRACT Biological processes that guard against melanoma are generally successful. Thus, to understand melanoma etiology we must identify the flaws in these mechanisms that lead to tumorigenesis. This proposal will elucidate deficiencies in the cellular mechanisms that combat UV damage and define the tumorigenic consequences of melanocyte pigment production. Our studies will improve mechanistic understanding of melanoma etiology by revealing gaps in the physiological processes that block UV carcinogenesis. We hypothesize that melanoma progression is influenced by melanin production and accelerated by the persistence of unresolved DNA lesions specific to the initiating UV wavelength. To test this hypothesis we will define how full-spectrum (UVA/B) and partitioned solar irradiation (UVA or UVB) influence the onset and progression of melanoma in genetically relevant, Braf- and Nras-mutant mouse models. We will elucidate transcriptional and mutational patterns enriched in tumors driven by each UV spectrum and oncogene, and use this information to define how UV lesions escape repair (Aim 1). Next, we will cross our models to eumelanotic (black), amelanotic (albino) or pheomelanotic (red/yellow) alleles to determine how melanin impacts the formation, progression and immunotherapeutic response of Braf- and Nras-mutant melanomas accelerated by different UV spectra (Aim 2). Knowledge gained from these experiments will aid in the development of melanoma preventatives that progress beyond sunscreens, including interventions that mitigate UV carcinogenesis after an exposure or reduce melanoma risk in individuals with more photosensitive skin types.

摘要