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（由申请人提供）：细胞命运是由在发育和细胞分化过程中以编程方式表达的基因集确定的。通常，在像糖尿病和癌症一样多样化的疾病中，转录调节剂出现异常的基因表达模式，这是疾病核心的核心。调节蛋白如何找到其结合位点并调节其靶向基因仍然是该领域的核心问题。 我们结合了化学和生物学方法，以研究转录调节剂的其他棘手特征。我们利用序列特异性DNA结合化合物（聚酰胺）来靶向特定的DNA序列，并且可以轻松地修改它们以具有丰富的功能模块。在拟议的工作中，我们将阐明由两个高度保守的发育调节剂内部和超弱索的合作DNA结合的基础。我们将采用这种理解来开发精确量身定制的合成调节剂，这些调节剂与细胞类型的特定转录因子合作针对基因。最后，我们将测试人工转录因子调节细胞和生物体中基因的能力。 我们工作的最终目标是生成可以以所需方式调节靶基因表达的小分子。作为设计师的转录因子，这些分子在解剖细胞命运和疾病的转录网络方面将具有巨大的价值。它们还具有作为由异常转录调节引起的多种疾病的治疗剂的潜力。