Gene-specific transcriptional silencing by REST function

通过 REST 功能进行基因特异性转录沉默

• 批准号: 10237940
• 负责人: Yan Jessie Zhang
• 金额: $ 31.89万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10237940
• 关键词: Address; Adult; Automobile Driving; Biochemical; Biological Assay; Biology; Biophysics; Brain Neoplasms; Cells; Chemicals; Chromatin Structure; Communication; Complex; Complication; DNA; Dependence; Development; Diagnosis; Disease; Dose; Elements; Enzymes; Funding; Gene Expression; Gene Proteins; Gene Silencing; Genes; Genetic Transcription; Glioblastoma; Grant; Intervention; Investigation; Life Expectancy; Measurement; Mediating; Molecular; Neuroglia; Neurons; Pathologic; Patients; Phosphoric Monoester Hydrolases; Promoter Regions; Property; RE1-silencing transcription factor; Reach, Effectiveness, Adoption, Implementation, and Maintenance; Regulation; Reporting; Repression; Research; Resolution; Role; Series; Structure; Testing; biophysical analysis; cell type; cytotoxic; design; dosage; genetic corepressor; genetic regulatory protein; histone modification; inhibitor/antagonist; nervous system disorder; overexpression; personalized medicine; protein complex; recruit; small molecule inhibitor; stem cells; structural biology; tool; transcription factor; transcription factor REST; tumor growth

PROJECT SUMMARY The RE-1 silencing transcription factor (REST), also known as Neuron-Restrictive Silencer Factor (NRSF), is a master regulator that represses the expression of neuronal genes in stem cell and non-neuronal cells. Overexpression of REST leads to the development of several types of brain tumors, and its dysregulation has been detected in multiple neurological diseases. The huge discrepancy arises reporting different genes subject to REST control, which might be due to the dose- and cell type-dependency of REST in different contexts. In this grant, we will test the hypothesis that REST transcriptional silencing activity can be controlled by small molecule inhibitors of the regulatory protein of REST we have developed. Particularly, we will investigate the cytotoxic effect of these inhibitors in glioblastoma cells when REST drives tumor growth. Furthermore, we will understand at the atomic level the molecular mechanism of REST function through quantitative assessment of its interaction with its DNA targets and its co-repressors for gene silencing. In the long run, we want to identify small molecule inhibitors to treat diseases driven by excess REST activity.

项目摘要 RE-1沉默转录因子（静止），也称为神经受血限制性沉默因子 （NRSF）是一种主要调节剂，可抑制干细胞和非神经元细胞中神经元基因的表达。 休息的过表达会导致几种类型的脑肿瘤的发展，并且其失调具有 在多种神经系统疾病中检测到。巨大的差异会出现，报告不同的基因 休息控制，这可能是由于在不同上下文中休息的剂量和细胞类型依赖性。在这个 Grant，我们将检验以下假设：静止转录沉默活性可以由小分子控制 我们开发的静止蛋白的抑制剂。特别是，我们将研究细胞毒性 当休息驱动肿瘤生长时，这些抑制剂在胶质母细胞瘤细胞中的作用。此外，我们将了解 在原子水平上，通过定量评估其相互作用，REST功能的分子机制 其DNA靶标及其共抑制剂用于基因沉默。从长远来看，我们要识别小分子 抑制剂治疗由过度休息活动驱动的疾病。