Epigenetic Regulation of Cutaneous Tumorigenesis

皮肤肿瘤发生的表观遗传调控

• 批准号: 10661669
• 负责人: David Chen
• 金额: $ 23.58万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661669
• 关键词: Academic Medical Centers; Academic support; Acute Myelocytic Leukemia; Affect; Age; Aging; Award; Basal Cell; Biological Markers; Blood Cells; C57BL/6 Mouse; Cancer Patient; Cancerous; Carcinoma; Cell Aging; Cells; Clinical; Clonal Expansion; Cutaneous; Cytokeratin-14 Staining Method; DNA; DNA Damage; DNA Methylation; DNA Modification Methylases; DNA Sequence Alteration; DNMT3B gene; DNMT3a; Data; Development; Diagnosis; Disease; Elderly; Enterobacteria phage P1 Cre recombinase; Enzymes; Epidemiology; Epidermis; Epigenetic Process; Event; Exhibits; Exposure to; Gene Expression; Gene Expression Profile; Genes; Genetic; Genomics; Goals; Growth; Human; In Vitro; Individual; Induced Mutation; Island; KRAS2 gene; KRASG12D; LoxP-flanked allele; Lung Neoplasms; Malignant Neoplasms; Mediating; Mentors; Mentorship; Methylation; Methyltransferase; Methyltransferase Gene; Modeling; Mus; Mutagens; Mutate; Mutation; Names; Neoplastic Cell Transformation; Oncogenic; Pathogenesis; Pathway interactions; Patient Care; Patients; Persons; Phenotype; Physicians; Population; Predisposition; Prevention; Process; Program Development; Property; Proto-Oncogenes; Recurrence; Research; Research Personnel; Research Project Grants; Resources; Risk; Risk Factors; Role; Scientist; Skin; Skin Aging; Skin Cancer; Somatic Mutation; Squamous cell carcinoma; Study models; Testing; Transgenic Model; UVB induced; Ultraviolet Rays; United States; Universities; Up-Regulation; Washington; Work; age related; aged; bisulfite sequencing; cancer genomics; carcinogenesis; career; career development; cell age; chemical carcinogenesis; design; epigenetic regulation; improved; in vivo; insight; keratinocyte; loss of function mutation; medical schools; mouse model; next generation sequencing; normal aging; novel strategies; novel therapeutics; pancreatic neoplasm; premalignant; promoter; single-cell RNA sequencing; skin organogenesis; tumor; tumor initiation; tumorigenesis; whole genome; Academic Medical Centers; Academic support; Acute Myelocytic Leukemia; Affect; Age; Aging; Award; Basal Cell; Biological Markers; Blood Cells; C57BL/6 Mouse; Cancer Patient; Cancerous; Carcinoma; Cell Aging; Cells; Clinical; Clonal Expansion; Cutaneous; Cytokeratin-14 Staining Method; DNA; DNA Damage; DNA Methylation; DNA Modification Methylases; DNA Sequence Alteration; DNMT3B gene; DNMT3a; Data; Development; Diagnosis; Disease; Elderly; Enterobacteria phage P1 Cre recombinase; Enzymes; Epidemiology; Epidermis; Epigenetic Process; Event; Exhibits; Exposure to; Gene Expression; Gene Expression Profile; Genes; Genetic; Genomics; Goals; Growth; Human; In Vitro; Individual; Induced Mutation; Island; KRAS2 gene; KRASG12D; LoxP-flanked allele; Lung Neoplasms; Malignant Neoplasms; Mediating; Mentors; Mentorship; Methylation; Methyltransferase; Methyltransferase Gene; Modeling; Mus; Mutagens; Mutate; Mutation; Names; Neoplastic Cell Transformation; Oncogenic; Pathogenesis; Pathway interactions; Patient Care; Patients; Persons; Phenotype; Physicians; Population; Predisposition; Prevention; Process; Program Development; Property; Proto-Oncogenes; Recurrence; Research; Research Personnel; Research Project Grants; Resources; Risk; Risk Factors; Role; Scientist; Skin; Skin Aging; Skin Cancer; Somatic Mutation; Squamous cell carcinoma; Study models; Testing; Transgenic Model; UVB induced; Ultraviolet Rays; United States; Universities; Up-Regulation; Washington; Work; age related; aged; bisulfite sequencing; cancer genomics; carcinogenesis; career; career development; cell age; chemical carcinogenesis; design; epigenetic regulation; improved; in vivo; insight; keratinocyte; loss of function mutation; medical schools; mouse model; next generation sequencing; normal aging; novel strategies; novel therapeutics; pancreatic neoplasm; premalignant; promoter; single-cell RNA sequencing; skin organogenesis; tumor; tumor initiation; tumorigenesis; whole genome

Project Summary/Abstract: This proposal describes a five-year career development program designed to support an academic, physician- scientist career. The proposed research project will capitalize on the expertise and resources available at Washington University School of Medicine, which has a strong tradition of developing physician-scientists. Dr. Timothy Ley, an expert in cancer genomics and epigenetics, and a recipient of multiple mentorship awards nationally and at Washington University, will serve as the primary research mentor. The ultimate goal of the candidate is to be an independent investigator in an academic medical center, studying epigenetic control of cutaneous carcinogenesis, and caring for patients with cutaneous malignancies. The long-term goal of this study is to define alterations in the epigenetic “state” of epidermal keratinocytes that arise during normal aging and their roles in creating age-related susceptibilities for skin cancer. Increasing age and UV light exposure are the two most prominent epidemiologic risk factors for the development of skin cancer in fair skinned populations. Recent studies have identified clonal expansions of cells harboring oncogenic mutations from clinically normal skin, suggesting that additional genetic or epigenetic events are required for transformation to skin cancer. Aging and UV light exposure not only cause DNA damage and mutations, but also have been demonstrated to cause DNA methylation changes in the skin of human patients; whether these alterations are relevant for skin cancer pathogenesis is currently unknown. Our preliminary data suggests that the DNA methylation state of epidermal cells undergoes a programmed change at specific loci in mice as they age, as do stereotypical changes in gene expression resulting in the development of a population of cells that we have named “basal aging-signature keratinocytes” (BASKs). We will explore the hypothesis that age-related epigenetic changes, including DNA methylation, may increase susceptibility to skin cancer development with the following specific aims: Aim 1: We will define the epigenetic events in murine epidermis that result from normal aging, relate them to functional changes, and assess their roles in the development of skin cancers. We will define the epigenetic changes in BASK cells, define biomarkers that allow for the purification of this population, and test the susceptibility of aged skin to KRASG12D- mediated skin tumorigenesis and the development of UVB-induced, mutated Trp53 clonal islands in the skin. Aim 2: We will define the roles of individual DNA methyltransferases for the development of age-dependent methylation states and for the neoplastic transformation of skin. Using mice conditionally deficient in Dnmt1, Dnmt3a, and/or Dnmt3b in epidermal cells, we will determine whether these enzymes contribute to age-related development of the BASK phenotype, and whether their deficiencies are relevant for KRASG12D-mediated skin tumorigenesis. If successful, insights gained from this work may allow for the creation of novel therapeutic or preventative approaches for the keratinocyte cancers, basal cell and squamous cell carcinoma.

项目摘要/摘要： 该建议描述了一项五年的职业发展计划，旨在支持学术，身体 科学家职业。拟议的研究项目将利用可用的专业知识和资源 华盛顿大学医学院，具有发展身体科学家的悠久传统。博士 蒂莫西·莱伊（Timothy Ley），癌症基因组学和表观遗传学专家，并获得了多个Mentalship Awards的获得者 全国和华盛顿大学将担任主要研究导师。最终目标 候选人将成为学术医学中心的独立研究员，研究对 皮肤致癌，并照顾患有皮肤恶性肿瘤的患者。 这项研究的长期目标是定义表皮表观遗传“状态”的变化 在正常衰老期间出现的角质形成细胞及其在创造与年龄相关的敏感性方面的作用 皮肤癌。年龄增加和紫外线暴露是两个最突出的流行病学风险因素 皮肤癌种群中皮肤癌的发展。最近的研究已经确定了克隆扩张 带有临床正常皮肤致癌突变的细胞，表明额外的遗传或表观遗传 转化为皮肤癌需要事件。衰老和紫外线暴露不仅引起DNA 损伤和突变，但也已被证明会导致皮肤的DNA甲基化变化 人类患者；目前，这些改变与皮肤癌发病机理有关。我们的 初步数据表明，表皮细胞的DNA甲基化状态经历了编程的变化 在小鼠的特定局部情况下，基因表达的刻板印象变化导致 我们称其为“基础老化 - 签名角质形成细胞”（BASKS）的细胞群的发展。我们 将探讨以下假设：与年龄相关的表观遗传变化（包括DNA甲基化）可能会增加 以下特定目的对皮肤癌发展的敏感性：目标1：我们将定义表观遗传 正常衰老导致的鼠表皮事件与功能变化有关，并评估其功能变化 在皮肤癌的发展中的作用。我们将定义BASK细胞的表观遗传变化，定义 允许纯化该人群并测试皮肤对Krasg12d-的敏感性的生物标志物 介导的皮肤肿瘤发生以及UVB诱导的突变的TRP53克隆岛的发育。 目的2：我们将定义单个DNA甲基转移酶的作用 甲基化状态和皮肤的肿瘤转化。使用有条件缺陷DNMT1的小鼠， 表皮细胞中的DNMT3A和/或DNMT3B，我们将确定这些酶是否有助于与年龄有关 BASK表型的发展，以及它们的缺陷是否与Krasg12d介导的皮肤有关 肿瘤发生。如果成功的话，这项工作获得的见解可能会允许创建新颖的疗法或 角质形成细胞癌，碱性细胞和鳞状细胞癌的预防方法。