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: 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
• 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

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.

项目总结/文摘

项目成果

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

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
• 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