Epigenetic Regulators in Epidermal Homeostasis and Neoplasia

描述（由申请人提供）：我的长期目标是花一个职业生涯指导一个富有成效的研究实验室教学的学生和研究员，同时作出重大贡献上皮生物学。特别是，我对细胞如何分化成不同的发育谱系并保留细胞记忆感兴趣。我感兴趣的表皮作为一个模型系统，因为皮肤有一个恒定的周转率与增殖和分化的周期。这些周期必须严格调节，否则就会迅速出现紊乱。我也对这些基本过程的失调如何导致人类疾病如癌症感兴趣。 这个培训计划将帮助我实现这些目标，因为我将学习解决计划中的问题的所有技术和技能。具体来说，在此期间的培训将为我提供上皮生物学，体内哺乳动物模型系统，基因组学和癌症生物学的新专业知识。我的近期目标是实现下文所述的提案目标。 表皮稳态是一个严格调节的过程，其开始于活跃分裂的细胞，这些细胞最终分化成形成皮肤的不透水层的去核角质细胞。生长和分化之间平衡的扰动可导致各种人类皮肤疾病。增殖增加和分化减少可导致过度增殖性疾病，如银屑病、基底细胞癌或鳞状细胞癌。因此，全面了解表皮生长和分化的调节因子将是解开皮肤病潜在的分子机制的关键，这可能会导致皮肤病的靶向治疗的发展。这项工作的目的是确定表皮生长，分化和肿瘤形成的表观遗传修饰剂的作用。 我们以前的研究结果表明，组蛋白去甲基化酶，JMJD 3，控制表皮分化，通过去除甲基标记的H3K27me3标记的表皮分化基因启动子。由于JMJD3在表皮分化中的中心作用，JMJD3的功能改变可能有助于瘤形成。目的研究JMDJ3在人表皮肿瘤发生发展中的作用。 为了鉴定在表皮生长和分化中具有作用的其他表观遗传修饰剂，我们系统地耗尽了DNA和组蛋白修饰酶的功能，并发现DNA甲基转移酶1（DNMT1）和组蛋白脱乙酰基酶2（HDAC2）对表皮生长和分化具有影响。目的II着重于表征DNMT 1和HDAC 2在表皮生长、分化和肿瘤形成中的作用。

DESCRIPTION (provided by applicant): My long-term goal is to spend a career guiding a productive research laboratory teaching students and fellows while making significant contributions to epithelial biology. In particular, I am interested in how cells differentiate into different developmental lineages and retain that cellular memory. I am interested in the epidermis as a model system since the skin has a constant turnover rate with cycles of proliferation and differentiation. These cycles must be tightly regulated or disorders would rapidly arise. I am also interested in how dysregulation of these fundamental processes can lead to human diseases such as cancer. This training proposal will help me attain these goals because of all the techniques and skills I will learn to address the questions of the proposal. Specifically, the training during this award period will provide me with new expertise in epithelial biology, in vivo mammalian model systems, genomics, and cancer biology. My immediate goal is to accomplish the aims of the proposal as described below. Epidermal homeostasis is a tightly regulated process that begins with actively dividing cells that eventually differentiate into enucleated corneocytes that form the water-impermeable layer of the skin. Perturbations in the balance between growth and differentiation can lead to a variety of human skin disorders. Increased proliferation and diminished differentiation can lead to hyperproliferative disorders such as psoriasis, basal or squamous cell carcinomas. Thus, a comprehensive understanding of the regulators of epidermal growth and differentiation would be key to unlocking the molecular mechanisms underlying skin disorders which could potentially lead to the development of target guided therapies for skin disorders. This effort aims to define the role of epigenetic modifiers in epidermal growth, differentiation, and neoplasia. Our previous findings demonstrated that the histone demethylase, JMJD3, controls epidermal differentiation by removal of methyl marks on H3K27me3 marked epidermal differentiation gene promoters. Because of the central role of JMJD3 in epidermal differentiation, functional alterations in JMJD3 may contribute to neoplasia. Aim I will characterize the role of JMDJ3 in human epidermal tumor progression. In order to identify other epigenetic modifiers with a role in epidermal growth and differentiation, we systematically depleted the function of DNA and histone modifying enzymes and found DNA methyltransferase 1 (DNMT1) and Histone deacetylase 2 (HDAC2) to have effects on epidermal growth and differentiation. Aim II focuses on characterizing the role of DNMT1 and HDAC2 on epidermal growth, differentiation and neoplasia.