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：
10676091
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/10676091
关键词：
Academic advising Acceleration 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 Learning Life Linear Models Link Lung Maps Mediating Memory Mentors Mission Modeling Molecular Biology 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 age stratification 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 mouse model novel personalized medicine progenitor programs research and development respiratory respiratory smooth muscle response risk sharing risk variant single-cell RNA sequencing skills therapeutic target tissue resident memory T cell 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.

项目摘要/摘要该建议概述了医学博士Nathan Schoettler博士的综合研究和职业发展计划在Carole Ober博士的实验室进行培训，并通过通过NIH指导的职业在遗传学和免疫学的界面上建立研究计划奖项（K08）。 PI最近完成了NIH T32奖学金（T32 HL007605），并接受了培训免疫学，遗传学，分子生物学和细胞生物学，在该K08奖的期间，PI将从其他院长（Dan Nicolae博士和Anne Sperling博士）和芝加哥大学的顾问（Julian Solway博士和Hae Kyung IM博士）。职业发展计划旨在为PI配备统计遗传学和细胞的必要知识和技能成功过渡到独立院士和R01资金的免疫学。总体目标拟议的研究是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部细胞类型。哮喘是一种复杂的遗传疾病，高遗传力，但是遗传变异如何影响病原体机制或内型，哮喘中没有已解决。 PI在其博士后T32期进行的研究表明，童年发病和成人哮喘具有共同的遗传风险基因座（Lancet Reves Med 2019）。 pi 此外，人类肺组织驻留记忆T细胞，这是不循环中的T细胞的子集血液的编程方式不同，源自单独的祖细胞与肺淋巴相比节点存储器T细胞子集（印刷中的COMM BIOL），它们迅速增加了关键哮喘的表达激活时细胞因子。这项K08研究建议检验了总体假设，即特定的哮喘亚下表型具有共同且独特的遗传危险因素，并且这些危险基因座介导细胞特异性的影响以独特的方式扰动基因表达和疾病风险的举止。 AIM 1将检验以下假设临床上重要的哮喘亚型型具有一组遗传风险变异，但还具有额外的，表型特异性遗传风险基因座。 AIM 2将检验以下假设：哮喘风险基因座的子集将藏有对肺组织驻留记忆T细胞中基因表达有独特作用的变异在其他组织或细胞类型中揭示。 AIM 3将检验以下假设，即哮喘亚表现型具有不同影响肺部与哮喘相关细胞中基因表达的一组风险基因座，特别是T细胞，光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表达定量性状基因座的结合研究在有和没有哮喘的气道细胞中鉴定相关暴露，并导致对遗传风险变异如何影响细胞的机械理解反应，最终揭示了潜在的治疗靶标。该职业奖将加速 Schoettler博士担任独立医师科学家，并获得竞争性R01资金。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

New Insights Relating Gasdermin B to the Onset of Childhood Asthma.

关于 Gasdermin B 与儿童哮喘发病的新见解。

DOI：
10.1165/rcmb.2022-0043ps
发表时间：
2022
期刊：
American journal of respiratory cell and molecular biology
影响因子：
6.4
作者：
Schoettler,Nathan;Dissanayake,Eishika;Craven,MarkW;Yee,JeremiahS;Eliason,Joshua;Schauberger,EricM;LemanskeJr,RobertF;Ober,Carole;Gern,JamesE
通讯作者：
Gern,JamesE

SARS-CoV-2 Infection Is Associated with Reduced Krüppel-like Factor 2 in Human Lung Autopsy.

DOI：
10.1165/rcmb.2020-0564le
发表时间：
2021-08
期刊：
American journal of respiratory cell and molecular biology
影响因子：
6.4
作者：
Wu D;Lee TH;Huang RT;D Guzy R;Schoettler N;Adegunsoye A;Mueller J;Husain A;I Sperling A;Mutlu GM;Fang Y
通讯作者：
Fang Y

A series of COVID-19 autopsies with clinical and pathologic comparisons to both seasonal and pandemic influenza.

DOI：
10.1002/cjp2.220
发表时间：
2021-09
期刊：
The journal of pathology. Clinical research
影响因子：
0
作者：
McMullen P;Pytel P;Snyder A;Smith H;Vickery J;Brainer J;Guzy R;Wu D;Schoettler N;Adegunsoye A;Sperling A;Hart J;Alpert L;Chang A;Gurbuxani S;Krausz T;Husain AN;Mueller J
通讯作者：
Mueller J

Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region.

DOI：
10.1038/s41467-021-26347-z
发表时间：
2021-10-21
期刊：
Nature communications
影响因子：
16.6
作者：
Aneas I;Decker DC;Howard CL;Sobreira DR;Sakabe NJ;Blaine KM;Stein MM;Hrusch CL;Montefiori LE;Tena J;Magnaye KM;Clay SM;Gern JE;Jackson DJ;Altman MC;Naureckas ET;Hogarth DK;White SR;Gomez-Skarmeta JL;Schoetler N;Ober C;Sperling AI;Nóbrega MA
通讯作者：
Nóbrega MA

Genome-wide association study identifies TNFSF15 associated with childhood asthma.

DOI：
10.1111/all.14952
发表时间：
2022-01
期刊：
Allergy
影响因子：
12.4
作者：
Kim KW;Kim DY;Yoon D;Kim KK;Jang H;Schoettler N;Kim EG;Kim MN;Hong JY;Lee JK;Kim S;Ober C;Gee HY;Sohn MH
通讯作者：
Sohn MH