Single-Cell Transcriptomic Analysis to Identify Drivers of Pulmonary Fibrosis

单细胞转录组分析识别肺纤维化的驱动因素

基本信息

批准号：
10112301
负责人：
Paul A Reyfman
金额：
$ 16.28万
依托单位：
NORTHWESTERN UNIVERSITY AT 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：
2020-02-20 至 2021-07-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112301
关键词：
Address Aging Alveolar Alveolar Macrophages Automobile Driving Award Biochemical Biological Process Bleomycin Bronchoalveolar Lavage Fluid Cell Nucleus Cells Chronic lung disease Cicatrix Clinical Data Communities Computing Methodologies Connective Tissue Diseases Cryopreservation Data Data Analyses Data Set Development Diagnosis Diagnostic Digestion Disease Donor person Drug Exposure Ensure Environmental Exposure Epithelial Cells Fibroblasts Fibrosis Foundations Funding Future Gases Gene Expression Gene Expression Profiling Genes Genomics Goals Gold Health Heterogeneity Human Image Immunohistochemistry Impairment In Situ Hybridization Individual Investigation Knowledge Laboratories Lead Lung Lung Compliance Lung Transplantation Machine Learning Mentors Molecular Mus Occupational Exposure Patient Selection Patients Physicians Population Prediction of Response to Therapy Prognosis Protocols documentation Pulmonary Fibrosis RNA Reporting Research Personnel Sampling Scientist Selection for Treatments Small Nuclear RNA Specimen Structure of parenchyma of lung System Systemic Scleroderma Systems Biology Techniques Technology Testing Tissues Training Training Programs Work base biomarker development career career development cell type clinical care clinical phenotype clinical practice computerized tools design differential expression effective therapy experimental study genomic data idiopathic pulmonary fibrosis improved individual patient insight macrophage monocyte mouse model new therapeutic target novel novel marker novel strategies personalized approach predicting response recruit risk stratification single cell analysis single-cell RNA sequencing skills tool transcriptome sequencing transcriptomics treatment response

项目摘要

PROJECT SUMMARY This proposal for a K08 Award is motivated by two overarching goals: 1) to support the scientific and professional development of the candidate, Dr. Paul Reyfman, towards achieving his career goal of succeeding as a physician scientist and independent investigator with expertise in systems biology approaches applied to the study of chronic lung disease, and 2) to investigate whether single-cell transcriptomic profiling can provide novel insights into the pathobiology of pulmonary fibrosis. Pulmonary fibrosis is a deadly and progressive condition for which diagnostic approaches remain imprecise and effective therapies are lacking. Together with his mentors, Drs. Scott Budinger and Luís Amaral, the candidate has developed a comprehensive training plan that will ensure Dr. Reyfman acquires new knowledge and proficiencies in developing hypotheses, designing and completing experiments, analyzing data, and communicating findings to the scientific community. As an essential component of this training plan, the candidate will employ systems biology approaches to developing tools for analysis of single-cell transcriptomic datasets generated from patients with pulmonary fibrosis. Single-cell transcriptomic profiling is increasingly used to investigate the pathobiology of disease in humans and as a basis for developing novel biomarkers of disease. Developing and validating tools for analyzing the rapidly growing quantity of single-cell transcriptomic data is as much of a challenge as refining techniques for generating data from healthy and diseased tissues. In particular, it is not known whether analysis of single-cell RNA sequencing (scRNA-Seq) and single-nucleus RNA sequencing (snRNA-Seq) data can be used to quantify accurately the cellular composition of the lung and to identify gene expression differences between health and pulmonary fibrosis. Our preliminary data suggest that scRNA-Seq of lung identifies profibrotic gene expression in patients with pulmonary fibrosis that is heterogeneous between individuals. We also found that scRNA-Seq undersampled certain constituent lung cellular populations. Accordingly, we designed this proposal to test the hypothesis that single-cell transcriptomic analysis of lung samples from patients with pulmonary fibrosis can be used to identify disease endotypes. In Specific Aim 1, the candidate will determine whether snRNA-Seq enables quantification of the cellular composition of the lung during pulmonary fibrosis. In Specific Aim 2, the candidate will develop tools for using scRNA-Seq performed on specimens obtained from patients with SSc-ILD and normal controls to gain novel insights into disease pathobiology. Over the course of this award, the candidate will gain new skills including in generating snRNA-Seq from cryopreserved lung tissue, in lung stereology, in RNA in situ hybridization, in analysis of complementary genomic datasets, and in incorporation of clinical phenotypic information into genomic analyses. Accomplishing the proposed work will provide a rigorous training program for Dr. Reyfman and will provide insights that could lead to improved therapies for patients with pulmonary fibrosis.

项目摘要这项针对K08奖的建议是由两个总体目标的激励：1）支持科学和专业候选人保罗·雷夫曼（Paul Reyfman）博士的发展，以实现他作为物理学的继承目标具有系统生物学方法专业知识的科学家和独立研究者应用于研究慢性肺病和2）研究单细胞转录组是否可以提供新颖的见解进入肺纤维化病理生物学。肺纤维化是一种致命而渐进的疾病诊断方法仍然是暗示的，缺乏有效的疗法。与他的导师博士一起。候选人Scott Budinger和LuísAmaral制定了一项全面的培训计划，以确保博士雷夫曼（Reyfman 实验，分析数据并将发现与科学界传达。作为重要组成部分在本培训计划中，候选人将采用系统生物学方法来开发工具来分析来自肺纤维化患者产生的单细胞转录组数据集。单细胞的转录组分析越来越多地用于研究人类疾病的病理学和作为发展新型疾病生物标志物的基础。开发和验证快速分析工具增加数量的单细胞转录组数据与精炼技术一样，是一个挑战来自健康和解剖组织的数据。特别是，尚不清楚单细胞RNA的分析是否测序（SCRNA-SEQ）和单核RNA测序（SNRNA-SEQ）数据可用于量化准确地确定肺的细胞组成并确定健康与健康之间的基因表达差异肺纤维化。我们的初步数据表明，肺的SCRNA-SEQ鉴定了纤维纤维化基因表达在肺纤维化的患者中，个体之间是异质的。我们还发现Scrna-Seq 不足采样了某些成分肺细胞种群。根据，我们设计了此建议以测试假设肺纤维化患者的肺样本的单细胞转录组分析可以是用于鉴定疾病内型。在特定的目标1中，候选人将确定SNRNA-Seq是否启用肺纤维化期间肺部细胞组成的定量。在特定目标2中，候选人将开发用于使用从SSC-ild和正常患者获得的标本上执行的SCRNA-SEQ的工具控制疾病病理生物学的新颖见解。在此奖项的过程中，候选人将获得新技能，包括从冷冻保存肺组织，肺立体原理中产生snRNA-seq，在RNA原位杂交，分析完整的基因组数据集和临床表型的掺入信息中的基因组分析。完成拟议的工作将为严格的培训计划 Reyfman博士，将提供有关肺纤维化患者的治疗方法的见解。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Study protocol for a national cohort of adults focused on respiratory health: the American Lung Association Lung Health Cohort (ALA-LHC) Study.

DOI：
10.1136/bmjopen-2021-053342
发表时间：
2021-07-05
期刊：
BMJ open
影响因子：
2.9
作者：
Reyfman PA;Sugar E;Hazucha H;Hixon J;Reynolds C;Bose S;Dransfield MT;Han MK;Estepar RSJ;Rice MB;Washko GR;Carnethon M;Kalhan R;American Lung Association Airways Clinical Research Network;American Lung Association Airway’s Clinical Research Network
通讯作者：
American Lung Association Airway’s Clinical Research Network

Determinants of SARS-CoV-2 receptor gene expression in upper and lower airways.

DOI：
10.1101/2020.08.31.20169946
发表时间：
2020-09-02
期刊：
medRxiv : the preprint server for health sciences
影响因子：
0
作者：
Aliee, H;Massip, F;Faiz, A
通讯作者：
Faiz, A

Determinants of expression of SARS-CoV-2 entry-related genes in upper and lower airways.

DOI：
10.1111/all.15152
发表时间：
2022-03
期刊：
Allergy
影响因子：
12.4
作者：
Aliee H;Massip F;Qi C;Stella de Biase M;van Nijnatten J;Kersten ETG;Kermani NZ;Khuder B;Vonk JM;Vermeulen RCH;U-BIOPRED study group;Cambridge Lung Cancer Early Detection Programme;INER-Ciencias Mexican Lung Program;Neighbors M;Tew GW;Grimbaldeston MA;Ten Hacken NHT;Hu S;Guo Y;Zhang X;Sun K;Hiemstra PS;Ponder BA;Mäkelä MJ;Malmström K;Rintoul RC;Reyfman PA;Theis FJ;Brandsma CA;Adcock IM;Timens W;Xu CJ;van den Berge M;Schwarz RF;Koppelman GH;Nawijn MC;Faiz A
通讯作者：
Faiz A

Care Fragmentation Is Associated with Increased Chronic Obstructive Pulmonary Disease Exacerbations in a U.S. Urban Care Setting.

在美国城市护理环境中，护理碎片化与慢性阻塞性肺疾病加重有关。

DOI：
10.1164/rccm.202112-2807le
发表时间：
2022
期刊：
American journal of respiratory and critical care medicine
影响因子：
24.7
作者：
Young,KarenC;Meza,DanielA;Khuder,Basil;Rosenberg,SharonR;Liu,GabrielleY;Kruser,JacquelineM;Reyfman,PaulA;Kalhan,Ravi
通讯作者：
Kalhan,Ravi

Mortality from COVID-19 in Patients with COPD: A US Study in the N3C Data Enclave.