Genetics of Asthma Sub-Phenotypes Impact Gene Regulation in Cell-Specific Patterns

项目总结/摘要 该提案概述了一个综合的研究和职业发展计划内森Schoettler，医学博士，博士， 在Carole Ober博士的实验室进行培训，并通过以下方式过渡到独立学术职位 在遗传学和免疫学的界面上建立一个研究项目，并由NIH指导职业生涯 奖励（K 08）。PI最近完成了NIH T32奖学金（T32 HL 007605），并接受了以下领域的培训 免疫学，遗传学，分子生物学和细胞生物学，在此K 08奖期间，PI将 接受额外的共同导师（丹·尼古拉博士和安妮·斯珀林博士）的额外学术指导， 芝加哥大学的顾问（Julian Solway博士和Hae Kyung Im博士）职业发展计划 旨在使PI具备统计遗传学和细胞遗传学方面的必要知识和技能。 免疫学成功过渡到一个独立的院士，和R 01资金。的总目标 这项研究旨在阐明遗传变异在调节基因表达中的作用， 在哮喘中起关键作用的特定肺细胞类型。哮喘是一种复杂的遗传性疾病， 然而，遗传变异如何影响哮喘的病理生物学机制或内型， 已经解决了。PI在博士后T32阶段进行的研究表明，童年- 发作型和成人发作型哮喘具有共同和不同的遗传风险位点（Lancet Resp Med 2019）。的PI 进一步表明，人类肺组织驻留记忆T细胞，一个不循环的T细胞亚群， 血液程序不同，且来源于与肺引流淋巴不同的祖细胞库 淋巴结记忆T细胞亚群（Comm Biol，出版中），它们迅速增加关键哮喘 激活时的细胞因子。这项K 08研究提案测试了特定哮喘亚组的总体假设， 表型有共同的和不同的遗传风险因素，这些风险基因座介导的细胞特异性的影响， 以独特的方式扰乱基因表达和疾病风险。目标1将检验以下假设： 临床上重要的哮喘亚表型共享一组遗传风险变体，但也有额外的亚表型， 表型特异性遗传风险位点。目标2将检验一个假设，即一个子集的哮喘风险位点将隐藏 这种变异对肺组织驻留记忆T细胞中的基因表达具有独特的影响， 在其他组织或细胞类型中发现。目的3将检验哮喘亚表型具有不同表型的假设， 一组影响肺部哮喘相关细胞（特别是T细胞）基因表达的风险位点， 肌肉细胞和上皮细胞。这项研究的目标将通过整合全基因组 与在有和没有哮喘的气道细胞中鉴定的表达数量性状基因座的关联研究- 相关暴露，并导致对遗传风险变异如何影响细胞的机制性理解 反应，最终揭示潜在的治疗靶点。这一职业奖将加速过渡， 博士Schoettler成为一名独立的物理学家和科学家，并获得了竞争性的R 01资金。

PROJECT SUMMARY/ABSTRACT This proposal outlines an integrated research and career development plan for Nathan Schoettler, MD, PhD to conduct training in the laboratory of Dr. Carole Ober and transition to an independent academic position by establishing a research program at the interface of genetics and immunology with a NIH mentored career award (K08). The PI recently completed an NIH T32 fellowship (T32 HL007605) and is trained in the fields of immunology, genetics, molecular biology and cell biology, and during the time of this K08 award, the PI will receive additional academic guidance from additional co-mentors (Dr. Dan Nicolae and Dr. Anne Sperling) and advisors (Dr. Julian Solway, and Dr. Hae Kyung Im) at the University of Chicago. The career development plan is designed to equip the PI with the necessary knowledge and skills in statistical genetics and cellular immunology for a successful transition to an independent academician, and R01 funding. The overall goal of the proposed research is to elucidate the role of genetic variation in regulating the expression of genes in specific lung cell types that play a critical role in asthma. Asthma is a complex genetic disease with high heritability, yet how genetic variation influences pathobiological mechanisms, or endotypes, in asthma has not been resolved. Studies conducted by the PI during his post-doctoral T32 phase demonstrated that childhood- onset and adult-onset asthma have both shared and distinct genetic risk loci (Lancet Resp Med 2019). The PI furthermore showed that human lung tissue resident memory T cells, a subset of T cells that do not circulate in the blood, are programmed differently and derived from a separate pool of progenitor than lung-draining lymph node memory T cell subsets (Comm Biol, in press), and they rapidly increase the expression of key asthma cytokines when activated. This K08 research proposal tests the overall hypothesis that specific asthma sub- phenotypes have shared and distinct genetic risk factors and that these risk loci mediate effects in cell-specific manners that perturb gene expression and disease risk in unique ways. Aim 1 will test the hypothesis that clinically important asthma sub-phenotypes share a set of genetic risk variants but also have additional, sub- phenotype-specific genetic risk loci. Aim 2 will test the hypothesis that a subset of asthma-risk loci will harbor variation that has unique effects on gene expression in lung tissue resident memory T cells that have not been revealed in other tissues or cell types. Aim 3 will test the hypothesis that asthma sub-phenotypes have different sets of risk loci that influence gene expression in asthma-relevant cells from lungs, specifically T cells, smooth muscle cells and epithelial cells. The goals of this research will be achieved by integrating genome-wide association studies with expression quantitative trait loci identified in airway cells with and without asthma- relevant exposures, and lead to a mechanistic understanding of how genetic risk variants influence cellular responses, ultimately revealing potential therapeutic targets. This career award will accelerate the transition for Dr. Schoettler to an independent physician-scientist and the acquisition of competitive R01 funding.