权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Molecular Mechanism of UV Protection in Cutaneous Melanoma

皮肤黑色素瘤紫外线防护的分子机制

基本信息

批准号：
10542439
负责人：
Chengyu Liang
金额：
$ 62.23万
依托单位：
WISTAR INSTITUTE
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：
2020-07-29 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10542439
关键词：
Acceleration Address Autophagocytosis Biochemistry Biogenesis Biological Assay CRISPR/Cas technology Cells Chemoresistance Clinical Complex Cutaneous Melanoma DNA Sequence Alteration Data Deposition Dermatology Development Disease Environment Epidemiology Etiology Future Gene Expression Gene Mutation Gene Targeting Genes Genetic Genetic Induction 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 Process Production Prognostic Marker Publishing Radiation induced damage Recurrence 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 radiation-resistance associated gene UV sensitive UV-induced melanoma Ultraviolet Rays Validation Work Xenograft Model candidate identification fitness gene interaction gene repression 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 prognostication repaired resistance gene response risk prediction screening single molecule skin disorder tumor tumor growth ubiquitin ligase ultraviolet lesions unpublished works

项目摘要

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.

项目摘要来自阳光的紫外线辐射(UVR)已被流行病学确定为患上心脏病的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存在。正在被阐明。最近的研究揭示了大量紫外线诱导的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。这些研究强调了需要更好地了解防止环境紫外线诱变的分子机制，以及描述为什么它们在黑色素瘤中不起作用，提供可能为个性化铺平道路的答案预防和治疗这种往往致命的疾病。该项目将迎接这一挑战，利用我们的最近发现的自噬调节剂作为真正的紫外线保护剂通过不同的机制和它与降低黑色素瘤风险有很强的相关性。我们的主要假设是，紫外线的容量减少诱导性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，并对黑色素瘤易感性负责。为了检验这一假设，我们首先剖析黑素细胞修复紫外线诱导的光渗漏以提供紫外线的机制抗性(目标1)，确定紫外线诱导黑素合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的影响方式和影响程度可诱导转基因和人源化小鼠对黑色素瘤的紫外线敏感性和肿瘤生长模型(目标3)。这些目标将使用多学科的创新方法来实现，这些方法包括最新的遗传学、生物化学、活细胞成像和细胞和小鼠的生理分析抗紫外线基因的靶向突变。我们预计，我们的研究将发现新的紫外线-- 调节黑色素瘤疾病外显性并在体内提供令人信服的保护机制一种新的黑色素瘤预后和预测生物标志物的有效性。