Characterizing the comprehensive gene regulatory basis of autoimmunity.

表征自身免疫的综合基因调控基础。

• 批准号: 10231450
• 负责人: Diego Calderon
• 金额: $ 6.37万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231450
• 关键词: Address; Affect; Architecture; Autoimmune; Autoimmune Diseases; Autoimmunity; Binding Proteins; Biochemical; Biological; Biological Assay; Butter; Cell Line; ChIP-seq; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; Complex; Coupled; Data; Data Analyses; Development; Disease; Drug Targeting; Encapsulated; Encyclopedia of DNA Elements; Enhancers; Experimental Designs; Fellowship; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Enhancer Element; Genetic Transcription; Genomic Segment; Genomics; Genotype; Goals; Health; Human; Individual; Institution; Lead; Light; Mass Spectrum Analysis; Measures; Mediating; Methods; Nucleic Acid Regulatory Sequences; Pathway interactions; Phenotype; Proteins; Quantitative Trait Loci; Regulation; Regulator Genes; Regulatory Element; Reporter; Research; Research Personnel; Research Proposals; Research Training; Resources; Risk; Role; Science; Therapeutic; Training; Trans-Activators; Universities; Untranslated RNA; Washington; base; experimental study; flexibility; genetic architecture; genetic regulatory protein; genetic variant; genome sciences; genome-wide; high risk; method development; multimodal data; next generation; novel strategies; skills; tool; trait; transcription factor

Project Summary Enhancers are fundamental gene regulatory elements with critical roles in development and disease, and yet relatively little is known about how enhancers themselves are regulated. What are the upstream gene pathways important for activating enhancers? Which proteins bind to an enhancer and modulate proximal gene expression? How do these regulatory factors affect complex phenotypes? While large-scale efforts such as the Encyclopedia of DNA Elements (ENCODE) Consortium have made laudable progress towards a compendium of enhancers, we lack the tools necessary to understand enhancer regulation, and more broadly, its role in disease. To address this critical shortcoming, I will first develop a new, high-throughput method — a trans massively parallel reporter assay or transMPRA — that can address current limitations of identifying protein-regulatory element interactions in a scalable manner. I will then apply transMPRA, along with other high-throughput genomics assays and multimodal data analysis, to reveal the comprehensive gene-regulatory basis of autoimmunity. I anticipate that this new method together with findings from its initial application will have broad implications toward understanding the role of gene regulation in complex traits including human autoimmune disorders. In addition to my research proposal, I will undergo a fellowship training plan that continues to refine my skills as a researcher and active contributor to the science community. The proposed research and fellowship training plan will take place in the labs of my sponsor and co-sponsor, Dr. Jay Shendure and Dr. Cole Trapnell, in the Department of Genome Sciences at University of Washington. I specifically chose my advisors and institution because they have an outstanding track record of performing cutting edge research and training the next generation of science thought leaders.

项目摘要 增强子是基因调节元素，在发育和疾病中起关键作用，但 关于增强剂本身如何监管的知之甚少。上游基因途径是什么 激活增强剂很重要吗？蛋白质与增强子结合并调节近端基因 表达？这些调节因素如何影响复杂的表型？而大规模的努力，例如 DNA元素（编码）财团的百科全书取得了值得称赞的进步 在增强器中，我们缺乏了解增强器调节所需的工具，更广泛地是其在 疾病。 为了解决这个关键的缺点，我将首先开发一种新的高通量方法 - 一种大规模的跨性别方法 并行记者测定或传染性测定法 - 可以解决识别蛋白质调节的当前局限性 元素以可扩展的方式相互作用。然后，我将应用Transmpra以及其他高通量 基因组学测定和多模式数据分析，以揭示 自身免疫性。我预计这种新方法以及其初始应用程序的发现将具有广泛的 对理解基因调节在包括人自身免疫在内的复杂性状中的作用的启示 疾病。 除了我的研究建议外，我还将接受一项奖学金培训计划，继续完善我的技能 研究人员和积极的科学界贡献者。拟议的研究和奖学金培训 计划将在我的赞助商和共同发起人Jay Shendure博士和Cole Trapnell博士的实验室中进行。 华盛顿大学基因组科学系。我特别选择了我的顾问和机构 因为他们在下一个执行尖端研究和训练的良好记录 科学思想领导者的一代。