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

基本信息

批准号：
10457974
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
项目类别：
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/10457974
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

项目摘要

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.

项目概要/摘要该提案概述了 Nathan Schoettler 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，并通过以下方式过渡到独立的学术职位在 NIH 指导下建立遗传学和免疫学交叉领域的研究项目奖（K08）。该 PI 最近完成了 NIH T32 奖学金 (T32 HL007605)，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，在获得 K08 奖项期间，PI 将接受其他共同导师（Dan Nicolae 博士和 Anne Sperling 博士）的额外学术指导，以及芝加哥大学的顾问（Julian Solway 博士和 Hae Kyung Im 博士）。职业发展计划旨在让 PI 具备统计遗传学和细胞学方面必要的知识和技能免疫学成功过渡为独立院士，并获得 R01 资助。总体目标为拟议的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遗传性，但遗传变异如何影响哮喘的病理生物学机制或内型尚未可知已解决。 PI 在博士后 T32 阶段进行的研究表明，童年- 发病和成人发病的哮喘都有共同和不同的遗传风险位点（Lancet Resp Med 2019）。 PI 此外还表明，人类肺组织中存在常驻记忆 T 细胞，这是 T 细胞的一个子集，不会在肺组织中循环。与肺引流淋巴液相比，血液的编程方式不同，并且源自不同的祖细胞池节点记忆 T 细胞亚群（Comm Biol，出版中），它们迅速增加关键哮喘的表达当细胞因子被激活时。这项 K08 研究计划测试了总体假设，即特定哮喘亚型表型具有共同且不同的遗传风险因素，并且这些风险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 将检验以下假设：临床上重要的哮喘亚表型共享一组遗传风险变异，但也有其他亚表型表型特异性遗传风险位点。目标 2 将检验哮喘风险位点子集将隐藏的假设这种变异对肺组织常驻记忆 T 细胞的基因表达具有独特的影响，而这些细胞尚未被在其他组织或细胞类型中揭示。目标 3 将检验哮喘亚表型具有不同的假设影响肺部哮喘相关细胞（特别是 T 细胞）基因表达的风险基因座组，平滑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患有和不患有哮喘的气道细胞中鉴定的表达数量性状位点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械理解反应，最终揭示潜在的治疗靶点。该职业奖将加速转型 Schoettler 博士成为一名独立医师科学家并获得了具有竞争力的 R01 资金。