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Mechanisms of small molecule gene transcriptional regulators

小分子基因转录调控机制

基本信息

批准号：
10242743
负责人：
RICHARD R NEUBIG
金额：
$ 37.58万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242743
关键词：
Actins Address BCL3 gene Binding Biochemical Biophysics Bromodomain Calorimetry Cell Nucleus Cell Proliferation Cell physiology Clinical Complex Crystallization DNA Data Development Disease EGR2 gene Elements Enhancers Environment Epigenetic Process Family Fibrosis Future GTP-Binding Proteins Gene Expression Regulation Genetic Genetic Transcription Goals HSF1 Histone Deacetylase Histone Deacetylase Inhibitor Immediate-Early Genes In Vitro Inflammatory Interleukin-6 JUN gene Knockout Mice Luciferases Malignant Neoplasms Mediating Molecular Mechanisms of Action Molecular Target Myofibroblast Neoplasm Metastasis Nuclear Protein Oxidation-Reduction Paper Pathway interactions Pharmacology Phenotype Play Proteins Publishing Pulmonary Fibrosis Reporter Role Scanning Scleroderma Serum Serum Response Factor Signal Transduction Small Interfering RNA Speed Structure Therapeutic Titrations Toll-like receptors Transcriptional Regulation Vinculin Work cancer cell cell motility connective tissue growth factor in vivo inhibitor/antagonist mouse model myocardin novel novel therapeutics p65 prevent promoter rho small molecule tool transcription factor

项目摘要

Summary Gene transcription signaling through RhoA- and actin-regulated transcription factors plays a critical role in diverse diseases such as cancer and fibrosis. Transcription factors downstream of RhoA and actin, serum response factor (SRF) and myocardin-related transcription factor (MRTF) controls cell proliferation, cancer cell migration and metastasis and the myofibroblast activation. We identified MRTF-pathway inhibitor compounds (e.g. CCG-1423 and CCG-203971) and recently identified the redox-sensitive nuclear protein pirin as a molecular target. This reveals pirin as a regulator of MRTF/SRF- and NFkB-regulated gene transcription providing a novel dual inhibitor mechanism for our CCG compounds relevant to cancer and fibrotic diseases by blocking both inflammatory and pro-fibrotic/proliferative signals. The overarching goal of this work is to explore the role of pirin and the mechanisms of CCG compounds in regulating gene transcription. The specific goals of this renewal application are to explore pirin’s actions on gene transcription regulated by RhoA/MRTF/SRF and NFB and to define the pirin-dependent and potentially pirin- independent molecular mechanisms of action of the CCG compounds. To accomplish this goal, we will address the following specific aims: Aim 1 Elucidate biochemically, pirin’s interactions with MRTF, SRF, p65, and their DNA complexes with a focus on the role of pirin redox state and the effects of pirin-modulating compounds on these mechanisms. Aim 2 Assess the role of pirin and the effects of CCG compounds in pro-fibrotic and inflammatory gene transcription mediated by MRTF/SRF, TGF-, Toll-like receptors (TLRs), and NFB by use of a novel pirin knock- out mouse model. Impact - Successful completion of these aims will reveal mechanisms and scope of gene regulation by pirin and how this may be influenced by the redox environment. It will also provide a mechanistic framework for future development of CCG compounds for clinical use in cancer and fibrotic diseases.

概括通过 RhoA 和肌动蛋白调节转录因子的基因转录信号在癌症和纤维化等多种疾病。 RhoA 和肌动蛋白下游转录因子、血清反应因子（SRF）和心肌素相关转录因子（MRTF）控制细胞增殖、癌细胞迁移和转移以及肌成纤维细胞激活。我们鉴定了 MRTF 通路抑制剂化合物（例如 CCG-1423 和 CCG-203971），最近鉴定出氧化还原敏感核蛋白 Pirin 作为分子靶标。这揭示了 Pirin 作为 MRTF/SRF 和 NFkB 调节基因转录的调节剂为我们与癌症和纤维化疾病相关的 CCG 化合物提供新型双重抑制剂机制通过阻断炎症和促纤维化/增殖信号。这项工作的总体目标是探索 Pirin 的作用以及 CCG 化合物在调节基因转录。该更新应用程序的具体目标是探索皮林对基因的作用转录受 RhoA/MRTF/SRF 和 NF+B 调节，并定义了 pirin 依赖性和潜在的 pirin- CCG 化合物的独立分子作用机制。为了实现这一目标，我们将实现以下具体目标：目标 1 重点阐明 pirin 与 MRTF、SRF、p65 及其 DNA 复合物的生化相互作用关于皮林氧化还原态的作用以及皮林调节化合物对这些机制的影响。目标 2 评估 Pirin 的作用以及 CCG 化合物对促纤维化和炎症基因的影响 MRTF/SRF、TGF-β、Toll 样受体 (TLR) 和 NFβB 通过使用新型 Pirin 敲入介导的转录出鼠标模型。影响 - 成功完成这些目标将揭示皮林和基因调控的机制和范围这如何受到氧化还原环境的影响。它还将为未来提供一个机制框架开发用于癌症和纤维化疾病临床应用的 CCG 化合物。