Epigenetic Regulation of Cutaneous Tumorigenesis

皮肤肿瘤发生的表观遗传调控

• 批准号: 10223237
• 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/10223237
• 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; 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; exhaustion; 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： 该提案描述了一项为期五年的职业发展计划，旨在支持学术、医生- 拟议的研究项目将利用现有的专业知识和资源。 华盛顿大学医学院有着培养医生科学家的悠久传统。 Timothy Ley，癌症基因组学和表观遗传学专家，多次获得导师奖 在全国和华盛顿大学，将担任主要研究导师的最终目标。 候选人将成为学术医学中心的独立研究者，研究表观遗传控制 皮肤癌的发生以及皮肤恶性肿瘤患者的护理。 这项研究的长期目标是确定表皮表观遗传“状态”的改变 正常衰老过程中产生的角质形成细胞及其在产生与年龄相关的敏感性方面的作用 皮肤癌。年龄增长和紫外线照射是两个最重要的流行病学危险因素。 最近的研究发现皮肤癌在皮肤白皙的人群中发生克隆扩张。 含有来自临床正常皮肤的致癌突变的细胞，表明额外的遗传或表观遗传 转变为皮肤癌需要发生一些事件，老化和紫外线照射不仅会导致 DNA。 损伤和突变，但也已被证明会导致皮肤 DNA 甲基化变化 人类患者；这些改变是否与皮肤癌发病机制相关目前尚不清楚。 初步数据表明表皮细胞的DNA甲基化状态发生了程序性变化 随着小鼠年龄的增长，在特定位点上，基因表达的典型变化也会导致 我们将其命名为“基础衰老特征角质形成细胞”（BASK）的细胞群的发育。 将探讨与年龄相关的表观遗传变化（包括 DNA 甲基化）可能增加的假设 皮肤癌发展的易感性具有以下具体目标： 目标 1：我们将定义表观遗传 小鼠表皮中由正常衰老引起的事件，将它们与功能变化联系起来，并评估它们的 我们将定义 BASK 细胞的表观遗传变化，定义其在皮肤癌发展中的作用。 允许纯化该人群并测试老化皮肤对 KRASG12D 敏感性的生物标志物- 介导皮肤肿瘤发生和 UVB 诱导的皮肤中 Trp53 克隆岛突变的形成。 目标 2：我们将定义个体 DNA 甲基转移酶在年龄依赖性发育中的作用 使用 Dnmt1 条件性缺陷的小鼠，进行甲基化状态和皮肤肿瘤转化。 表皮细胞中的 Dnmt3a 和/或 Dnmt3b，我们将确定这些酶是否有助于年龄相关 BASK 表型的发展，以及它们的缺陷是否与 KRASG12D 介导的皮肤相关 如果成功，从这项工作中获得的见解可能有助于创造新的治疗或治疗方法。 角质形成细胞癌、基底细胞癌和鳞状细胞癌的预防方法。