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：
10436339
负责人：
RICHARD R NEUBIG
金额：
$ 37.54万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436339
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 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-和肌动蛋白调节的转录因子传导基因转录信号在多种疾病，例如癌症和纤维化。 Rhoa和肌动蛋白下游的转录因子，串行反应因子（SRF）和肌钙蛋白相关转录因子（MRTF）控制细胞增殖，癌细胞迁移和转移以及肌纤维细胞激活。我们确定了MRTF-Pathway抑制剂化合物（例如CCG-1423和CCG-203971），最近将氧化还原敏感的核蛋白pirin鉴定为一种分子靶标。这揭示了Pirin是MRTF/SRF-和NFKB调节的基因转录的调节剂为我们的CCG化合物提供与癌症和纤维化疾病有关的新型双抑制剂机制通过阻止炎症和促纤维化/增殖信号。这项工作的总体目标是探索Pirin的作用和CCG化合物的机制调节基因转录。此更新应用的具体目标是探索Pirin对基因的行为由RhoA/MRTF/SRF和NFB调节的转录，并定义pirin依赖性和潜在的pirin- CCG化合物作用的独立分子机制。为了实现这一目标，我们将解决以下特定目标： AIM 1从生物化学上阐明Pirin与MRTF，SRF，P65及其DNA复合物的相互作用，重点关于Pirin氧化还原状态的作用以及Pirin调节化合物对这些机制的影响。 AIM 2评估Pirin的作用以及CCG化合物在促纤维化和炎症基因中的作用通过MRTF/SRF，TGF-，Toll样受体（TLRS）和NFB介导的转录。鼠标模型。影响 - 成功完成这些目标将揭示Pirin和Pirin基因调节的机制和范围这可能会受到氧化还原环境的影响。它还将为未来提供机械框架开发用于癌症和纤维化疾病临床使用的CCG化合物。