Regulators of Epidermal Gene Expression

表皮基因表达的调节因子

• 批准号: 8617407
• 负责人: Xiaomin Bao
• 金额: $ 9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8617407
• 关键词: Affinity Chromatography; Basal cell carcinoma; Biological Process; Biology; Catalytic Domain; Cell Cycle; Cells; Chromatin Remodeling Factor; Chronic; Complex; Coupled; DNA; Development; Differentiation and Growth; Disease; Epidermis; Epithelial; Equilibrium; Event; Frequencies; Future; Gene Expression; Generations; Genes; Genomics; Goals; Growth; Homeostasis; Human; In Vitro; Lead; Light; Maintenance; Malignant Neoplasms; Manuscripts; Mass Spectrum Analysis; Molecular; Mutation; Natural regeneration; Nucleosomes; Patients; Phase; Phenocopy; Phosphorylation; Preparation; Process; Protein-Arginine N-Methyltransferase; Proteins; Psoriasis; RNA Splicing; Recurrence; Regulator Genes; Research; Role; SMARCC1 gene; SMARCC2 gene; Sampling; Science; Scientist; Specificity; Squamous cell carcinoma; Stem cells; Testing; Tissue Differentiation; Tissues; Training; Transcriptional Regulation; Undifferentiated; Wound Healing; base; career; chromatin remodeling; design; exome sequencing; human disease; human tissue; in vivo; insight; interest; keratinocyte; loss of function mutation; neoplastic; next generation; novel; pluripotency; progenitor; programs; protein complex; public health relevance; skin disorder; skin squamous cell carcinoma; tissue regeneration; tumor progression

Project Summary My long-term career goal is to lead a productive academic research group, promoting science by conducting active research on epithelial biology and nourishing the next generation of dedicated scientists. I am particularly interested in the mechanism underlying epidermal tissue homeostasis, which is tightly controlled by the balance between proliferation and differentiation. Disruptions of epidermal homeostasis underlie a number of diseases including psoriasis, chronic wound healing, and cancer. This K99/R00 proposal aims to define the role of chromatin remodeling during early epidermal tumor progression, and to uncover novel regulators essential for maintaining the epidermal progenitor state. First, we will focus on the role of the BAF/SWI/SNF chromatin remodeling complex in the earliest phases of epidermal tumor progression. Chromatin remodeling complexes directly impact gene expression by using the energy from ATP to disrupt the contact between DNA and nucleosomes. The BAF chromatin remodeling complex is composed of one catalytic subunit, Brg1 or Brm, and 10 interchangeable regulatory subunits encoded by 18 genes. Aim I will test the hypothesis that recurrent mutations in selected regulatory subunits of the BAF complex, which we have recently observed in squamous cell carcinoma (SCC), facilitate early cancer progression by impairing differentiation. We will do this by regenerating and characterizing human neoplastic tissue with altered function of BAF subunits. This effort is designed to yield insight into the mechanism underlying how the chromatin remodeling process is hijacked in cancer progression. Second, we will identify novel regulators that are required to maintain progenitors in epidermal tissue. We have recently identified the protein arginine methyltransferase, PRMT1, as dominantly required to sustain progenitor function. We have further identified 37 PRMT1-interacting proteins in undifferentiated primary human keratinocytes, through our recent PRMT1 protein complex purification. Aim II will identify and characterize new regulators among these PRMT1-interacting proteins in maintaining progenitor function, and will shed light on gene regulatory mechanisms underlying human tissue homeostasis. This proposal will define the role of the BAF chromatin remodeling complex in tumor progression, and will also identify new sustainers of epidermal progenitor function, as a basis for new therapies for diseases of skin and other tissues.

项目摘要 我的长期职业目标是领导一个富有成效的学术研究小组，通过开展 积极研究上皮生物学，培养下一代敬业的科学家。我是 尤其对表皮组织动态平衡的机制感兴趣，该机制由 增殖和分化之间的平衡。表皮动态平衡的破坏是许多 包括牛皮癣、慢性伤口愈合和癌症在内的各种疾病。本K99/R00提案旨在定义 染色质重塑在早期表皮肿瘤进展中的作用及发现新的调节因子 维持表皮祖细胞状态所必需的。 首先，我们将重点研究BAF/SWI/SNF染色质重塑复合体在早期阶段的作用 表皮肿瘤进展。染色质重塑复合体直接影响基因表达 来自三磷酸腺苷的能量，破坏DNA和核小体之间的接触。曝气生物滤池染色质重塑 复合体由一个催化亚基BRG1或BRM和10个可互换的调节亚基组成 由18个基因编码。目的我将检验这样一种假设，即选定的调节亚基中的反复突变 我们最近在鳞状细胞癌(SCC)中观察到的BAF复合体有助于早期癌症 通过损害分化而进展。我们将通过再生和表征人类肿瘤来做到这一点 BAF亚基功能改变的组织。这一努力旨在深入了解这一机制。 在癌症进展中染色质重塑过程是如何被劫持的。 其次，我们将确定维持表皮组织中的祖细胞所需的新型调控因子。我们 最近发现精氨酸甲基转移酶PRMT1蛋白主要需要维持 祖细胞功能。我们在未分化的原代细胞中进一步鉴定了37个与PRMT1相互作用的蛋白 人角质形成细胞，通过我们最新的PRMT1蛋白复合体纯化。AIM II将确定和 鉴定这些PRMT1相互作用蛋白中维持祖细胞功能的新调节因子，以及 将阐明人类组织动态平衡背后的基因调控机制。 该提案将确定BAF染色质重塑复合体在肿瘤进展中的作用，并将 也确定新的表皮祖细胞功能的支持因素，作为皮肤病新疗法的基础 和其他纸巾。