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

哮喘亚表型的遗传学影响细胞特异性模式中的基因调控

• 批准号: 10040104
• 负责人: Nathan R Schoettler
• 金额: $ 15.7万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10040104
• 关键词: Academic advising; Address; Adult; Affect; Age of Onset; Alleles; Area; Asthma; Asthma COPD Overlap Syndrome; Award; Blood; Cells; Cellular Immunology; Cellular biology; Chicago; Childhood; Chronic; Clinical; Complement; Complex; Coupling; Data; Development Plans; Disease; Doctor of Philosophy; Epithelial Cells; Evaluation; Fellowship; Foundations; Funding; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Risk; Genetic Variation; Genotype; Goals; Health; Heritability; Human; Human Resources; Immunology; Knowledge; Laboratories; Lead; Learning; Life; Linear Models; Link; Lung; Mediating; Memory; Mentors; Mission; Modeling; Molecular Biology; Mus; Pathogenesis; Pathway interactions; Pattern; Phase; Phenotype; Physicians; Play; Positioning Attribute; Postdoctoral Fellow; Public Health; Quantitative Trait Loci; RNA Splicing; Research; Research Personnel; Research Proposals; Resources; Risk; Role; Scientist; Smooth Muscle Myocytes; Structure of parenchyma of lung; T memory cell; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Time; Tissues; Training; Translating; United States National Institutes of Health; Universities; Variant; analytical method; asthmatic patient; biobank; bronchial epithelium; career; career development; causal variant; cell type; clinical care; clinical heterogeneity; cytokine; design; disability; disorder risk; draining lymph node; genetic association; genetic risk factor; genetic variant; genome wide association study; improved outcome; insight; novel; personalized medicine; progenitor; programs; research and development; respiratory; respiratory smooth muscle; response; risk sharing; risk variant; single-cell RNA sequencing; skills; therapeutic target; trait; transcriptome sequencing; translational study

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.

项目摘要/摘要 该提案概述了内森·舍特勒博士、医学博士和博士的综合研究和职业发展计划，以 在Carole Ober博士的实验室进行培训并过渡到独立的学术职位 在美国国立卫生研究院指导职业生涯中建立遗传学和免疫学相结合的研究项目 奖项(K08)。PI最近完成了NIH T32奖学金(T32 HL007605)，并在以下领域接受培训 免疫学、遗传学、分子生物学和细胞生物学，在K08奖期间，PI将 从其他共同导师(Dan Nicolae博士和Anne Sperling博士)那里获得额外的学术指导 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学方面的必要知识和技能 免疫学成功过渡为独立院士，并获得R01资助。的总目标是 这项研究的目的是阐明基因变异在基因表达调控中的作用。 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，具有较高的 遗传性，然而遗传变异如何影响哮喘的病理生物学机制或内型还没有 已经解决了。PI在他的博士后T32阶段进行的研究表明，童年- 发作性哮喘和成人型哮喘具有共同和不同的遗传风险基因(《柳叶刀·响应医学》2019年)。《少年派》 进一步表明，人类肺组织驻留记忆T细胞，T细胞的一个子集，不循环在 血液的程序不同，来自不同的祖细胞池，而不是肺排出的淋巴 节点记忆T细胞亚群(Comm Biol，正在出版中)，它们迅速增加了关键哮喘的表达 当细胞因子被激活时。这项K08研究提案测试了总体假设，即特定的哮喘亚组 表型有共同的和不同的遗传风险因素，这些风险基因位点介导细胞特异性的影响 以独特的方式扰乱基因表达和疾病风险的方式。目标1将检验假设 临床上重要的哮喘亚型共享一组遗传风险变异，但也有额外的亚型 表型特有的遗传风险基因座。目标2将检验这样的假设，即哮喘风险基因的子集将包含 对肺组织驻留记忆T细胞的基因表达有独特影响的变异 在其他组织或细胞类型中发现的。目标3将检验哮喘亚型具有不同表型的假设 影响肺部哮喘相关细胞，特别是T细胞基因表达的多组风险基因座 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来实现 与哮喘和非哮喘患者呼吸道细胞中确定的表达数量性状基因座的相关性研究 相关暴露，并导致对遗传风险变异如何影响细胞的机械性理解 反应，最终揭示潜在的治疗靶点。这一职业奖项将加速以下项目的过渡 舒特勒博士获得了一家独立的内科科学家，并获得了竞争性的R01资金。