Molecular Mechanism of UV Protection in Cutaneous Melanoma

皮肤黑色素瘤紫外线防护的分子机制

• 批准号: 10294255
• 负责人: Chengyu Liang
• 金额: $ 62.23万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-29 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10294255
• 关键词: Address; Autophagocytosis; Biochemistry; Biogenesis; Biological Assay; CRISPR/Cas technology; Cells; Chemoresistance; Clinical; Complex; Cutaneous Melanoma; DNA Sequence Alteration; Data; Deposition; Dermatology; Development; Disease; Down-Regulation; Epidemiology; Etiology; Future; Gene Expression; Gene Mutation; Gene Targeting; Genes; Genetic; Genome; Goals; Human; Image; In Vitro; Incidence; Individual; Laboratories; Lysosomes; Malignant Neoplasms; Mediating; Melanins; Melanogenesis; Melanoma Cell; Modeling; Molecular; Molecular Target; Mus; Mutagenesis; Mutate; Mutation; Nucleotide Excision Repair; Oncogenes; Organelles; Outcome; Pathogenesis; Pathway interactions; Patients; Penetrance; Penetration; Physiological; Pigmentation physiologic function; Pigments; Predisposition; Preventive screening; Process; Production; Prognostic Marker; Publishing; Radiation induced damage; Recurrence; Regulation; Resistance; Risk; Risk Factors; Risk Management; Skin; Skin Cancer; Skin Pigmentation; Sunlight; Technology; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Tumor Suppressor Proteins; UV Radiation Exposure; UV induced; UV induced DNA damage; UV protection; UV sensitive; UV-induced melanoma; Ultraviolet Rays; Validation; Work; Xenograft Model; base; fitness; gene interaction; genome editing; high risk; in vivo; in vivo Model; in vivo evaluation; individualized prevention; innovation; insight; live cell imaging; melanocyte; melanoma; melanomagenesis; mouse model; multidisciplinary; neoplastic; novel; personalized medicine; photolesion; predictive marker; prevent; prognostic; radiation resistance; repaired; resistance gene; response; risk prediction; screening; single molecule; skin disorder; tumor; tumor growth; ubiquitin ligase; ultraviolet lesions; unpublished works

Project Summary Ultraviolet radiation (UVR) from sunlight has been epidemiologically identified as a leading risk factor for melanoma development. However, the mechanistic details of how sunlight UVR causes melanoma are still being elucidated. Recent studies revealed tremendous amounts of UV-induced genetic mutations in melanoma genomes compared to most other types of tumors. Furthermore, UV-induced mutagenesis accelerates melanoma progression and recurrence. These studies highlighted the need to better understand the molecular mechanisms protecting against environmentally UVR-induced mutagenesis, and to delineate why they fail to work in melanoma, providing answers that could pave the way for personalized prevention and treatment of this often-fatal illness. This project will meet this challenge, capitalizing on our recent discovery of an autophagy modulator as a bona fide UV protector through distinct mechanisms and its strong correlation with reduced melanoma risk. Our primary hypothesis is that reduced capacity of UV- induced photolesion repair and adaptive skin pigmentation represents the main reasons of genetic instability of melanoma cells and is responsible for melanoma predisposition. To test the hypothesis, we will first dissect the mechanism by which UV-induced photolesion is repaired in melanocytes to provide UV resistance (Aim 1), identify the mechanism governing UV-induced melanogenesis and pigmentation to prevent UV penetration (Aim 2), and determine how and to what extent these mechanisms of action impact UV sensitivity and neoplastic expansion of melanoma using inducible transgenic and humanized murine models (Aim 3). These aims will be addressed using multidisciplinary innovative approaches that integrate state-of-the-art genetic, biochemistry, live-cell imaging, and physiological assays in cells and in mice with targeted mutations in UV resistance genes. Together, we anticipate that our studies will identify new UV- protecting mechanisms that regulate melanoma disease penetrance and provide compelling in vivo validation of a novel prognostic and predictive biomarker in melanoma.

项目概要 阳光中的紫外线辐射 (UVR) 已被流行病学确定为主要危险因素 黑色素瘤的发展。然而，阳光紫外线如何导致黑色素瘤的机制细节仍然未知。 正在被阐明。最近的研究揭示了紫外线诱导的大量基因突变 黑色素瘤基因组与大多数其他类型的肿瘤相比。此外，紫外线诱导的诱变 加速黑色素瘤的进展和复发。这些研究强调需要更好地 了解防止环境 UVR 诱导突变的分子机制，以及 描述为什么它们对黑色素瘤不起作用，提供可能为个性化治疗铺平道路的答案 预防和治疗这种常常致命的疾病。该项目将利用我们的优势来应对这一挑战 最近发现一种自噬调节剂通过不同的机制作为真正的紫外线保护剂 它与降低黑色素瘤风险密切相关。我们的主要假设是紫外线能力降低 诱导光损伤修复和适应性皮肤色素沉着是遗传不稳定的主要原因 黑色素瘤细胞并负责黑色素瘤的易感性。为了检验假设，我们首先 剖析黑素细胞中紫外线诱导的光损伤修复机制，以提供紫外线 抗性（目标 1），确定控制紫外线诱导的黑色素生成和色素沉着的机制 防止紫外线渗透（目标 2），并确定这些作用机制如何以及在何种程度上产生影响 使用诱导型转基因和人源化小鼠进行黑色素瘤的紫外线敏感性和肿瘤扩张 模型（目标 3）。这些目标将通过多学科创新方法来实现，这些方法将 在细胞和小鼠中进行最先进的遗传、生物化学、活细胞成像和生理测定 抗紫外线基因的靶向突变。我们预计我们的研究将确定新的紫外线- 调节黑色素瘤疾病外显率并提供令人信服的体内保护机制 验证黑色素瘤的新型预后和预测生物标志物。