Epigenetic control of target gene activity by hairless in skin homeostasis

无毛在皮肤稳态中对靶基因活性的表观遗传控制

• 批准号: 8700942
• 负责人: Liang Liu
• 金额: $ 11.64万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700942
• 关键词: Ablation; Alopecia; Apoptosis; Applications Grants; Award; Basic Science; Biological; Biological Assay; Biological Process; Biology; Biomedical Research; Candidate Disease Gene; Categories; Cell Cycle; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; ChIP-seq; Chromatin; Clinical; Clinical Research; Commit; Core Facility; Cutaneous; DNA; Dermal; Dermatology; Development; Differentiation and Growth; Disease susceptibility; Environment; Environmental Health; Environmental Risk Factor; Epidermis; Epigenetic Process; Exhibits; Functional disorder; Funding; Future; Gene Expression Profiling; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genome; Genomics; Goals; Growth; Hair; Hair follicle structure; Health; Histone H3; Histones; Homeostasis; Human; Hyperplasia; Institution; Laboratories; Lead; Lesion; Literature; Maps; Mentored Research Scientist Development Award; Mentors; Methods; Methylation; Molecular; Mutant Strains Mice; Mutation; National Institute of Environmental Health Sciences; PVT1 gene; Pathway interactions; Patients; Pattern; Play; Population; Postdoctoral Fellow; Process; Protein Family; Proteins; Publications; Regulation; Reporting; Research; Research Activity; Research Infrastructure; Research Personnel; Resistance; Resources; Role; S Phase; Scientist; Site; Skin; Skin Abnormalities; Stem cells; Stratum Basale; Structure; Subfamily lentivirinae; Testing; Transcriptional Regulation; UV induced; Universities; Wild Type Mouse; Work; Wound Healing; Writing; adult stem cell; base; career; demethylation; design; fibroblast growth factor 13; follow-up; improved; innovation; interest; keratinocyte; member; mutant; novel; programs; public health relevance; relating to nervous system; research study; self-renewal; skills; skin disorder; skin hyperplasia; small hairpin RNA; stem cell differentiation; stemness; tongue papilla; ultraviolet; ultraviolet irradiation

DESCRIPTION (provided by applicant): The Candidate for this K01 award, Dr. Liang Liu, joined the Department of Dermatology at Columbia University in July, 2010 as an Associate Research Scientist, where he studies epigenetic regulation of epidermal development and homeostasis under the direction of Dr. Angela Christiano, the Mentor of this K01 award. Dr. Liu's research interest centers on elucidating how genes and environment interact to influence development and disease susceptibility. The major goal of this project is to define the genetic and epigenetic pathways by which HR regulates epidermal growth and proliferation in skin homeostasis. Dr. Liu is committed to a biomedical research career. During the first two years of the award, he will focus on building up his research publication record and improving his skills in scientific writing including research articles and grant applications. From the third year of this K01 award, Dr. Liu will actively seek long-term funding support that will allow him to become a fully independent investigator after completion of this K01 award. Dr. Liu's long term career goal is to establish an innovative and independent research program in cutaneous biology. Institutional Environment Columbia University is one of the top research institutions in the US and has outstanding resources for trainees. There are state of the art laboratories for work in basic and clinical research and outstanding core facilities for supporting molecular and clinical research activities. The candidate's more immediate research environment is the Department of Dermatology and the Columbia University Skin Disease Research Center. He is also a member of the NIEHS Center for Environmental Health in Northern Manhattan, which provides additional resources and infrastructure that will facilitate the completion of this project. Research Summary Hairless (HR) belongs to the Jumonji C family of proteins, many of which function as histone demethylases (HDM) that participate in gene regulation via epigenetic mechanisms. We previously reported that mutations in HR are deleterious for skin homeostasis and hair follicle cycling, as exemplified by the clinical manifestations of patients with alopecia with papular lesions. We now have compelling evidence showing that HR is a HDM, regulating a subset of target genes through histone demethylation. We hypothesize that hairless acts as an epigenetic regulator of skin homeostasis via its downstream target genes to control cell proliferation and apoptosis. To test this hypothesis, we will focus on studying the role of hairless and its downstream target genes and pathways in epidermal growth and differentiation. We will employ molecular biological methods such as gene expression profiling, ChIP-Seq analysis, and comprehensive functional assays to rigorously test our hypothesis. Findings from this project will significantly enhance our understandings of the mechanisms underlying the pathophysiology of skin disorders such as hyperplasia and photoaging. The Candidate anticipates being able to complete the studies within a five-year award period through collaborative efforts with his Mentors and collaborators.

描述（由申请人提供）：本次K 01奖的候选人Liang Liu博士于2010年7月加入哥伦比亚大学皮肤科系，担任副研究科学家，在该K 01奖导师Angela Christiano博士的指导下研究表皮发育和稳态的表观遗传调控。刘博士的研究兴趣集中在阐明基因和环境如何相互作用影响发育和疾病易感性。该项目的主要目标是定义HR调节皮肤稳态中表皮生长和增殖的遗传和表观遗传途径。刘博士致力于生物医学研究事业。在该奖项的前两年，他将专注于建立他的研究出版记录，并提高他的技能， 科学写作，包括研究论文和资助申请。从K 01获奖的第三年开始，刘博士将积极寻求长期的资金支持，使他能够在完成K 01获奖后成为一名完全独立的研究者。刘博士的长期职业目标是在皮肤生物学领域建立一个创新和独立的研究项目。哥伦比亚大学是美国顶尖的研究机构之一，拥有优秀的培训资源。有最先进的基础和临床研究工作的实验室和支持分子和临床研究活动的优秀核心设施。候选人更直接的研究环境是皮肤科系和哥伦比亚大学皮肤病研究中心。他还是北方曼哈顿NIEHS环境健康中心的成员，该中心提供额外的资源和基础设施，将促进该项目的完成。无毛（HR）属于Jumonji C蛋白家族，其中许多蛋白作为组蛋白去甲基化酶（HDM）通过表观遗传机制参与基因调控。我们以前报道过HR突变对皮肤稳态和毛囊周期是有害的，如伴有丘疹性病变的脱发患者的临床表现。我们现在有令人信服的证据表明，HR是一种HDM，通过组蛋白去甲基化调节靶基因的子集。我们假设，无毛作为一个表观遗传调节皮肤稳态通过其下游靶基因控制细胞增殖和凋亡。为了验证这一假设，我们将重点研究无毛及其下游靶基因和途径在表皮生长和分化中的作用。我们将采用分子生物学方法，如基因表达谱分析，ChIP-Seq分析和综合功能测定来严格验证我们的假设。这个项目的发现将大大提高我们对皮肤疾病（如增生和光老化）病理生理学机制的理解。候选人期望能够通过与导师和合作者的合作，在五年的奖励期内完成研究。