权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Modular design of synthetic transcriptional regulators

合成转录调节因子的模块化设计

基本信息

批准号：
7569395
负责人：
ASEEM Z ANSARI
金额：
$ 24.47万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
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/7569395
关键词：
Animal Model Binding Binding Sites Biological Biology Cardiac Cell Line Cells Chemicals Chemistry Complement Cultured Cells DNA DNA Binding DNA Binding Domain DNA Sequence Defect Development Diabetes Mellitus Disease Docking Drosophila genus Embryo Family Gene Expression Gene Expression Regulation Gene Targeting Generations Genes Genetic Transcription Goals Heart Life Ligands Link Malignant Neoplasms Measures Membrane Modeling Molecular Conformation Molecular Medicine Monitor Nature Nylons Organism Pathway interactions Pattern Peptides Play Property Recruitment Activity Reporter Research Personnel Role Signal Transduction Site Specificity System Testing Therapeutic Agents Time Transcriptional Regulation Ursidae Family Work base cell type cellular development combinatorial cooperative study design driving force flexibility genetic regulatory protein genome-wide in vivo insight member next generation novel novel therapeutics programs promoter response small molecule success transcription factor

项目摘要

ell 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 n 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 specificDMA 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 oftargeted 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. The aslo have potential as therapeutic agents for a variety of diseases that are caused by aberrant transcriptional regulation.

细胞的命运是由一组基因决定的，这些基因在发育过程中以程序化的方式表达和细胞分化。通常，在糖尿病和癌症等多种疾病中，转录调节因子产生基因表达的异常模式，这是疾病的核心。调节蛋白如何找到它们的结合位点并调节它们的靶基因仍然是一个中心问题在球场上。我们将联合收割机化学和生物学方法结合起来，研究转录调控的其他棘手特征。监管部门我们利用序列特异性DNA结合化合物（聚酰胺）靶向特异性DNA 序列，并且它们可以容易地被修改以承载丰富的功能模块阵列。拟议本工作将阐明外齿体和超双胸体协同DNA结合的基础，保守的发育调节因子。我们将运用这种理解，与细胞类型特异性转录因子合作靶向基因的合成调节因子。最后我们将测试我们的人工转录因子在细胞和生物体中调节基因的能力。我们工作的最终目标是产生可以调节靶向表达的小分子。基因以所需的方式。作为设计转录因子，这些分子将具有巨大的价值，剖析控制细胞命运和疾病的转录网络。这些药物有治疗的潜力用于由异常转录调节引起的多种疾病的药剂。