Interpreting and Deploying Genomic Information During Animal Development

动物发育过程中基因组信息的解释和应用

• 批准号: 9923659
• 负责人: RICHARD S MANN
• 金额: $ 60.81万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-03 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923659
• 关键词: Address; Animals; Binding; Binding Sites; Biochemical; Biological; Cells; Code; DNA Sequence; Development; Disease; Distal; Drosophila genus; Epilepsy; Family; Gene Expression; Genes; Genetic; Genome; Genomics; Goals; Knowledge; Leg; Maps; Methods; Obesity; Specificity; Time; Work; experimental study; in vivo; personalized medicine; public health relevance; transcription factor

 DESCRIPTION (provided by applicant): The common theme underlying the questions being addressed in this proposal is how gene expression is controlled by cis-regulatory modules (CRMs) and the transcription factors that they bind during animal development. Answers to this question are becoming increasingly important in the emerging era of Personalized Medicine, since we now have the ability to sequence thousands of genomes and to identify changes in DNA sequences that correlate with diseases ranging from epilepsy to obesity. However, when changes in DNA sequence map to the non-protein coding portion of the genome, we are nearly helpless in interpreting these changes. This project will help bridge this gap in our knowledge by establishing methods to assess how the Hox family of transcription factors function in vivo. In the next several years, one goal is to extend what has been learned about Hox transcription factor specificity to a more in vivo level, in particular, to break the sequence code that allows these TFs to select biologically relevant binding sites in vivo. A second major goal is to understand at a deeper level how multiple transcription factors and CRMs coordinate with each other to regulate genes in the right cells and at the correct developmental time. For this last set of experiments, the focus is on how the proximo-distal axis of the Drosophila leg is established during development.

 描述（由申请人提供）：本提案中所解决问题的共同主题是基因表达如何由顺式调控模块（CRM）及其在动物发育过程中结合的转录因子控制。在新兴的个性化医疗时代，这个问题的答案变得越来越重要，因为我们现在有能力对数千个基因组进行测序，并识别与从癫痫到肥胖等疾病相关的 DNA 序列变化。然而，当 DNA 序列的变化映射到基因组的非蛋白质编码部分时，我们几乎无法解释这些变化。该项目将通过建立评估 Hox 转录因子家族如何在体内发挥作用的方法来帮助弥合我们的知识差距。在接下来的几年中，一个目标是将已经了解的 Hox 转录因子特异性扩展到体内水平，特别是打破允许这些转录因子在体内选择生物学相关结合位点的序列密码。第二个主要目标是更深入地了解多个转录因子和 CRM 如何相互协调，以在正确的发育时间调节正确细胞中的基因。对于最后一组 实验的重点是果蝇腿的近远端轴在发育过程中是如何建立的。