Diversity Supplement R01CA237213 - Mechanisms of UV-Mediated Melanoma Development

多样性补充 R01CA237213 - 紫外线介导的黑色素瘤发展机制

基本信息

批准号：
10514804
负责人：
Christin E Burd
金额：
$ 2.38万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10514804
关键词：
Alleles Award BRAF gene Biological Biological Process Cell Line Cells Cutaneous 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 Lead 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 Photosensitivity Physiological Physiological Processes Pigmentation physiologic function Pigments Prevention strategy Production Radiation Recording of previous events Relative Risks Research Residual state Risk Risk Factors Role Site Skin Sun Exposure Sunburn Sunlight Sunscreening Agents System Testing The Sun Transcription-Coupled Repair Tumor-infiltrating immune cells UV Mutagenesis UV Radiation Exposure UV carcinogenesis UV protection UV response Ultraviolet B Radiation Ultraviolet Rays Work combat exome sequencing experimental study human disease improved in vivo irradiation melanocyte melanoma mutant mutant mouse model pheomelanin repaired response transcriptome sequencing transcriptomics tumor tumor growth tumorigenesis tumorigenic ultraviolet ultraviolet damage ultraviolet lesions

项目摘要

SUMMARY (Parental Award) 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（家长奖）预防黑色素瘤的生物过程通常是成功的。因此，要了解黑色素瘤病因学我们必须找出这些导致肿瘤发生的机制中的缺陷。该提案将阐明对抗紫外线损伤和定义致瘤后果的细胞机制的缺陷黑色素细胞色素的产生。我们的研究将通过以下方式提高对黑色素瘤病因的机制理解：揭示阻止紫外线致癌的生理过程中的间隙。我们假设黑色素瘤的进展受到黑色素产生的影响，并由黑色素加速特定于起始紫外线波长的未解决的 DNA 损伤的持续存在。为了检验这个假设我们将定义全光谱 (UVA/B) 和分区太阳辐射（UVA 或 UVB）如何影响开始和遗传相关的 Braf 和 Nras 突变小鼠模型中黑色素瘤的进展。我们将阐明每种紫外线光谱和癌基因驱动的肿瘤中富集的转录和突变模式，以及使用此信息可定义紫外线损伤如何逃避修复（目标 1）。接下来，我们将把我们的模型交叉到真黑症（黑色）、无黑色素（白化病）或褐黑色素（红色/黄色）等位基因，以确定黑色素如何影响 Braf 和 Nras 突变黑色素瘤的形成、进展和免疫治疗反应加速不同的紫外光谱（目标 2）。从这些实验中获得的知识将有助于黑色素瘤的发展超越防晒霜的预防措施，包括在紫外线照射后减轻紫外线致癌的干预措施对于光敏感皮肤类型的人来说，暴露或减少黑色素瘤的风险。