Epigenetic control of target gene activity by hairless in skin homeostasis

简介(申请人提供)：K01奖项的候选人刘亮博士于2010年7月加入哥伦比亚大学皮肤科，担任副研究科学家，在K01奖项的导师Angela Christian博士的指导下研究表皮发育和动态平衡的表观遗传调控。刘博士的研究兴趣集中在阐明基因和环境如何相互作用来影响发育和疾病易感性。这个项目的主要目标是确定遗传和表观遗传途径，通过这些途径，HR在皮肤动态平衡中调节表皮生长和增殖。刘博士致力于生物医学研究事业。在奖项的头两年，他将专注于建立他的研究发表记录和提高他的技能 科学写作，包括研究文章和拨款申请。从这个K01奖项的第三年开始，刘博士将积极寻求长期的资金支持，使他在完成这个K01奖项后成为一名完全独立的研究员。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的、独立的研究项目。制度环境哥伦比亚大学是美国顶尖的研究机构之一，为学员提供了出色的资源。有最先进的基础和临床研究实验室，以及支持分子和临床研究活动的杰出核心设施。候选人更直接的研究环境是皮肤科和哥伦比亚大学皮肤病研究中心。他也是位于曼哈顿北部的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，将促进这一项目的完成。研究综述无毛(HR)属于Jumonji C蛋白家族，其中许多作为组蛋白去甲基酶(HDM)发挥功能，通过表观遗传机制参与基因调控。我们以前报道过HR基因突变对皮肤动态平衡和毛囊周期有害，有丘疹病变的脱发患者的临床表现就是例证。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来调节靶基因的一个子集。我们假设，无毛通过其下游靶基因控制细胞增殖和凋亡，发挥皮肤动态平衡的表观遗传调节作用。为了验证这一假说，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。我们将使用分子生物学方法，如基因表达谱、芯片序列分析和全面的功能分析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)的病理生理学基础的理解。候选人希望通过与导师和合作者的合作努力，能够在五年内完成学业。

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.