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 增强子是基本的基因调控元件，在发育和疾病中具有关键作用，然而， 关于增强子本身是如何被调节的，我们知之甚少。上游基因通路是什么 对激活增强子很重要吗哪些蛋白质与增强子结合并调节近端基因 表情？这些调控因子如何影响复杂的表型？虽然大规模的努力，如 DNA元素百科全书（ENCODE）联盟在编写一份简编方面取得了值得称赞的进展 我们缺乏必要的工具来了解增强子的调控，更广泛地说，它在 疾病 为了解决这个关键的缺点，我将首先开发一种新的，高通量的方法-一种大规模的反式 平行报告分析或transMPRA -可以解决目前鉴定蛋白质调节的局限性， 以可伸缩的方式进行元素交互。然后，我将应用transMPRA，沿着其他高通量 基因组学测定和多模式数据分析，以揭示全面的基因调控基础， 自身免疫我预计，这种新方法及其初步应用的结果将具有广泛的意义。 对理解基因调控在包括人类自身免疫在内的复杂性状中的作用的启示 紊乱 除了我的研究计划外，我还将参加一个奖学金培训计划，继续完善我的技能， 他是一位研究人员，也是科学界的积极贡献者。拟议的研究和研究金培训 计划将在我的赞助商和共同赞助商Jay Shendure博士和科尔特拉普内尔博士的实验室进行， 华盛顿大学基因组科学系。我特别挑选了我的顾问和机构 因为他们在进行前沿研究和培训下一代方面有着出色的记录， 一代科学思想领袖。