Regulators of Epidermal Gene Expression

表皮基因表达的调节因子

基本信息

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
项目类别：
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

项目摘要

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.

项目概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并培养下一代有奉献精神的科学家。我是对表皮组织稳态的机制特别感兴趣，该机制受到严格控制增殖与分化之间的平衡。表皮稳态的破坏是许多问题的根源疾病包括牛皮癣、慢性伤口愈合和癌症。该 K99/R00 提案旨在定义染色质重塑在早期表皮肿瘤进展过程中的作用，并发现新的调节因子对于维持表皮祖细胞状态至关重要。首先，我们将重点关注 BAF/SWI/SNF 染色质重塑复合物在染色质重塑最早阶段的作用表皮肿瘤进展。染色质重塑复合物通过使用直接影响基因表达 ATP 的能量破坏 DNA 和核小体之间的接触。 BAF染色质重塑复合物由 1 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。目的我将检验以下假设：选定的调节亚基中反复发生突变我们最近在鳞状细胞癌 (SCC) 中观察到的 BAF 复合物可促进早期癌症通过损害分化来进展。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。这项工作旨在深入了解该机制染色质重塑过程在癌症进展中如何被劫持的根本原因。其次，我们将确定维持表皮组织中祖细胞所需的新调节因子。我们最近发现蛋白质精氨酸甲基转移酶 PRMT1 是维持祖功能。我们进一步鉴定了未分化原代细胞中的 37 个 PRMT1 相互作用蛋白人类角质形成细胞，通过我们最近的 PRMT1 蛋白复合物纯化。目标 II 将确定并表征这些 PRMT1 相互作用蛋白中维持祖细胞功能的新调节因子，以及将揭示人体组织稳态的基因调控机制。该提案将定义 BAF 染色质重塑复合物在肿瘤进展中的作用，并将还确定了表皮祖细胞功能的新维持者，作为皮肤疾病新疗法的基础和其他组织。