Ethanol-induced skin changes

乙醇引起的皮肤变化

基本信息

批准号：
10304053
负责人：
Mayumi Fujita
金额：
$ 22.35万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304053
关键词：
Acetaldehyde Acetic Acids Alcohol consumption Alcohol dehydrogenase Alcohols Apoptosis Applications Grants Area Bar Codes Biology CYP2E1 gene Cells Cellular Stress Response Chronic DNA Damage Databases Diagnosis Environmental Risk Factor Enzymes Epidermis Ethanol Ethanol Metabolism Fibroblasts Future Gene Expression Genes Genetic Hepatocyte High Fat Diet Human In Situ Hybridization In Vitro Incidence Knockout Mice Lead Link Liquid substance Long-Term Effects Malignant Neoplasms Mediating Melanins Messenger RNA Microfluidics Mitochondria Modeling Mus Oxides Pathway interactions Patients Pattern Pharmacology Phenotype Poison Prevention strategy Process Prognosis Proliferating Proteins Reporting Risk Risk Factors Role Scheme Skin Skin Tissue Smoking Sun Exposure Testing The Cancer Genome Atlas The Sun UV Radiation Exposure UV induced UV induced DNA damage alcohol effect alcohol exposure aldehyde dehydrogenases biological adaptation to stress carcinogenesis chronic alcohol ingestion differential expression drinking epidemiologic data experimental study in vivo keratinocyte melanocyte melanoma mouse model new technology response single-cell RNA sequencing transcriptome ultraviolet

项目摘要

PROJECT SUMMARY/ABSTRACT The incidence of most cancers has declined, but that of melanoma continues to rise. About 200,000 new cases of melanoma will be diagnosed in 2020. Although one major risk ultraviolet (UV) exposure, not all forms of melanoma are related to sun factor linked to melanoma incidence is exposure or occur in sun-exposed areas. A better understanding of UV-unrelated risk factors will help in developing more effective preventative strategies for melanoma. Recent studies, including ours, have shown that alcohol consumption is positively linked to an increased risk of melanoma. However, no studies have tested this connection and elucidated the mechanisms in vitro and in vivo. Alcohol is first metabolized to acetaldehyde (AcAH) by alcohol dehydrogenase (ADH), and then oxidized to acetic acid by mitochondrial aldehyde dehydrogenase 2 (ALDH2). Alongside these two major enzymes, another enzyme, cytochrome p450 2E1 (CYP2E1), is involved in the conversion of alcohol to AcAH and then to acetic acid. To understand the relation between alcohol-metabolizing enzymes and melanoma, we used The Cancer Genome Atlas (TCGA) database and analyzed ADH (1A, 1B and 1C), ALDH2 and CYP2E1. We found a strong correlation between low expression of ALDH2 mRNAs and worse prognosis of melanoma patients. ALDH2 could be inactivated by many environmental factors. To understand the role for ethanol and inactivated ALDH2 in skin biology, we used ten-week-old Aldh2 KO mice. Because carcinogenesis is a chronic process, we used a mouse model of chronic alcohol consumption, where 3-5% and 10% (v/v) ethanol was provided as sole drinking fluid. Our preliminary experiments revealed a unique DNA damage pattern and melanocyte proliferation by ethanol in Aldh2 KO mice. In this grant application, we hypothesize that ethanol and/or AcAH induce cellular stress responses leading to melanocyte activation and dark CPD formation, and propose to define transcriptomes associated with ethanol-induced skin changes in mice (Aim 1) and the mechanisms of dark CPD formation by ethanol/AcAH in melanocytes (Aim 2). The effect of ethanol and/or acetaldehyde on skin changes has yet to be studied. Given the unique DNA damage induced by UV, our findings that ethanol induces melanocyte proliferation and UV-induced DNA damage without UV exposure warrant further phenotypic, functional and mechanistic studies, which will be further explored in future R01 applications.

项目概要/摘要大多数癌症的发病率已经下降，但黑色素瘤的发病率仍在上升。约20万新黑色素瘤病例将于 2020 年被诊断出来。尽管其中一项主要风险紫外线 (UV) 暴露，并非所有形式的黑色素瘤都与阳光有关与黑色素瘤发病率相关的因素是暴露或发生在阳光照射下地区。更好地了解与紫外线无关的风险因素将有助于开发更有效的预防措施黑色素瘤的策略。最近的研究（包括我们的研究）表明，饮酒对健康有积极影响。与黑色素瘤风险增加有关。然而，没有研究测试过这种联系并阐明体外和体内的机制。酒精首先被乙醇脱氢酶（ADH）代谢为乙醛（AcAH），然后氧化为线粒体乙醛脱氢酶 2 (ALDH2) 产生乙酸。除了这两种主要酶之外，另一种酶，细胞色素 p450 2E1 (CYP2E1)，参与酒精转化为 AcAH，然后转化为 AcAH。醋酸。为了了解酒精代谢酶和黑色素瘤之间的关系，我们使用了癌症基因组图谱 (TCGA) 数据库并分析了 ADH（1A、1B 和 1C）、ALDH2 和 CYP2E1。我们发现 ALDH2 mRNA 的低表达与黑色素瘤患者预后较差之间有很强的相关性。 ALDH2 可能会因许多环境因素而失活。了解乙醇和灭活剂的作用皮肤生物学中的ALDH2，我们使用十周龄的Aldh2 KO小鼠。因为癌变是一个慢性过程，我们使用了慢性饮酒的小鼠模型，其中提供 3-5% 和 10% (v/v) 乙醇唯一的饮用液体。我们的初步实验揭示了独特的 DNA 损伤模式和黑素细胞 Aldh2 KO 小鼠中乙醇的增殖。在此拨款申请中，我们假设乙醇和/或 AcAH 诱导细胞应激反应，导致黑素细胞激活和暗 CPD 形成，并提出定义与乙醇诱导的小鼠皮肤变化相关的转录组（目标 1）及其机制乙醇/AcAH 在黑素细胞中形成深色 CPD（目标 2）。乙醇和/或乙醛对皮肤变化的影响还有待研究。赋予独特的DNA 紫外线引起的损伤，我们发现乙醇会诱导黑素细胞增殖和紫外线诱导 DNA 在没有紫外线照射的情况下造成的损害需要进一步的表型、功能和机制研究，这将是在未来的 R01 应用中进一步探索。