Modular design of synthetic transcriptional regulators

合成转录调节因子的模块化设计

• 批准号: 7030370
• 负责人: ASEEM Z ANSARI
• 金额: $ 25.26万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7030370
• 关键词: DNA; DNA binding protein; Drosophilidae; biomimetics; developmental genetics; drug design /synthesis /production; embryo /fetus; gene expression; genetic regulation; ligands; nucleic acid sequence; protein binding; small molecule; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Cell fate is determined by sets of genes that are expressed in a programmed manner during development and cellular differentiation. Often, in diseases as diverse as diabetes and cancer, malfunctioning transcriptional regulators produce aberrant patterns of gene expression that are at the heart of the ailment. How regulatory proteins find their binding sites and regulate their targeted genes remains a central question in the field. We combine chemical and biological approaches to study otherwise intractable features of transcriptional regulators. We utilize sequence-specific DNA binding compounds (polyamides) to target specific DNA sequences, and they can be readily modified to bear a rich array of functional modules. In the proposed work, we will elucidate the basis of cooperative DNA binding by Extradenticle and Ultrabithorax, two highly conserved developmental regulators. We will apply that understanding to develop precisely tailored synthetic regulators that target genes cooperatively with cell-type specific transcription factors. Finally, we will test the ability of our artificial transcription factors to regulate genes in cells and in living organisms. The ultimate goal of our work is to generate small molecules that can regulate the expression of targeted genes in a desired manner. As designer transcription factors, these molecules will have tremendous value in dissecting transcriptional networks that govern cell fate and disease. They also have potential as therapeutic agents for a variety of diseases that are caused by aberrant transcriptional regulation.

描述(申请人提供)：细胞命运由发育和细胞分化过程中以程序化方式表达的一组基因决定。通常，在糖尿病和癌症等各种各样的疾病中，转录调控系统失灵会产生基因表达的异常模式，这是疾病的核心。调控蛋白如何找到它们的结合部位并调节它们的目标基因仍然是该领域的一个中心问题。 我们结合化学和生物学的方法来研究转录调控因子的其他难以处理的特征。我们利用序列特异的DNA结合化合物(聚酰胺)来靶向特定的DNA序列，它们可以很容易地进行修饰，以承载丰富的功能模块阵列。在拟议的工作中，我们将阐明牙外和超双胸这两种高度保守的发育调节因子协同结合DNA的基础。我们将应用这一理解来开发精确定制的合成调节剂，与细胞类型的特定转录因子合作靶向基因。最后，我们将测试我们的人工转录因子调节细胞和活体中基因的能力。 我们工作的最终目标是产生能够以所需方式调节目标基因表达的小分子。作为设计转录因子，这些分子在解剖控制细胞命运和疾病的转录网络方面将具有巨大的价值。它们也有潜力作为治疗各种疾病的药物，这些疾病是由异常转录调控引起的。