权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Applying Innovative Lung Mapping Strategies to Understand Alveolar Capillary Barrier Permeability in ARDS

应用创新的肺标测策略来了解 ARDS 中的肺泡毛细血管屏障渗透性

基本信息

批准号：
10650403
负责人：
Julie Anne Bastarache
金额：
$ 70.21万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
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：
2020-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650403
关键词：
Acute Acute Respiratory Distress Syndrome Acute respiratory failure Affect Alveolar American Biological Models Blood capillaries Catalogs Cells Clinical Trials Coupled Data Death Rate Development Disease Functional disorder Future Gene Expression Gene Expression Profile Goals Health Human Impairment In Vitro Institution Laboratories Life Lung Maps Mediator Methods Mission Modeling Molecular Mus National Heart, Lung, and Blood Institute Pathogenesis Pathologic Pathology Patients Permeability Phenotype Pre-Clinical Model Proteins Research Resources Sepsis Statistical Methods Structure of parenchyma of lung Testing Tissues Transgenic Model Transgenic Organisms Translating Translational Research Translations clinically relevant cost design flexibility human model in vivo injured innovation insight lung injury mass spectrometric imaging mortality mouse model new therapeutic target novel novel strategies novel therapeutics pre-clinical preclinical study programs protein expression single-cell RNA sequencing systems research targeted treatment therapeutic target

项目摘要

Project Summary This R35 application describes a robust research framework to facilitate discovery and translation of new therapeutic targets in Acute Respiratory Distress Syndrome (ARDS), a common cause of acute respiratory failure that carries a high mortality rate and has no beneficial targeted therapies. ARDS remains a significant health problem affecting 190,000 Americans per year, costing billions of dollars, and leaving the majority of patients dead or significantly impaired. New insights into the pathogenesis are needed to deepen our understanding of the underlying mechanisms that lead to ARDS as well as to develop novel therapeutics. Thus, there is an unmet need to define clinically relevant therapeutic targets that can be studied mechanistically and rapidly carried through robust pre-clinical studies. For the last 14 years I have been building my research team to be on the forefront of translational discovery. My group has made major contributions to understanding ARDS pathophysiology. The major focus of my laboratory is defining the key cellular and molecular regulators of alveolar capillary barrier function and dysfunction that underlies ARDS pathology. My R35 research program is designed to identify novel mediators in ARDS using lung tissue imaging mass spectrometry and deep phenotyping of gene expression profiles at the single cell level coupled with advanced statistical methods to identify leading targets. New targets will be studied in in vitro transgenic model systems to define cellular and molecular mechanisms in order to facilitate the development of novel therapeutics to be tested in pre-clinical models. My research framework is centered on three goals: Discovery, Mechanism and Translation. Goal 1 – Discovery. To accomplish this goal, we will break new ground using imaging mass spectrometry and single cell RNA sequencing to create an expression profile and protein “map” of the injured and uninjured human lung. Using advanced statistical approaches, we will identify promising targets to take forward into further studies. Goal 2 – Mechanism. Leveraging our existing lung injury models, institutional resources and new approaches, we will define the fundamental pathologic mechanisms that lead to alveolar capillary barrier permeability in ARDS by generating novel transgenic cell and mouse lines for mechanistic studies. Goal 3 – Translation. Building on our existing ex vivo human lung and in vivo mouse models, we will generate rigorous pre-clinical data based on new targets identified in our Discovery and Mechanism studies. With this R35, my lab will advance the mission of the NHLBI by: generating a catalogue of single cell transcription profiles and tissue protein expression levels in acutely injured and uninjured human lung, identifying novel therapeutic targets in ARDS, defining the cellular and molecular mechanisms regulating alveolar capillary barrier dysfunction and conducting pre-clinical studies in mouse and human models. The R35 will provide the support and flexibility necessary for me to break new ground in ARDS.

项目总结

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A preclinical systematic review and meta-analysis assessing the effect of biological sex in lipopolysaccharide-induced acute lung injury.

临床前系统评价和荟萃分析，评估生物性别对脂多糖诱导的急性肺损伤的影响。

DOI：
10.1152/ajplung.00336.2023
发表时间：
2024
期刊：
American journal of physiology. Lung cellular and molecular physiology
影响因子：
0
作者：
Kuhar,Eva;Chander,Nikesh;Stewart,DuncanJ;Jahandideh,Forough;Zhang,Haibo;Kristof,ArnoldS;Bastarache,JulieA;Schmidt,EricP;Taljaard,Monica;Thébaud,Bernard;Engelberts,Doreen;Fergusson,DeanA;Lalu,ManojM
通讯作者：
Lalu,ManojM

Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors: A Secondary Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis Randomized Clinical Trial.

DOI：
10.1001/jamanetworkopen.2023.0380
发表时间：
2023-02-01
期刊：
JAMA network open
影响因子：
13.8
作者：
通讯作者：

LNK/SH2B3 loss of function increases susceptibility to murine and human atrial fibrillation.

LNK/SH2B3 功能丧失会增加小鼠和人类房颤的易感性。

DOI：
10.1093/cvr/cvae036
发表时间：
2024
期刊：
Cardiovascular research
影响因子：
10.8
作者：
Murphy,MatthewB;Yang,Zhenjiang;Subati,Tuerdi;Farber-Eger,Eric;Kim,Kyungsoo;Blackwell,DanielJ;Fleming,MatthewR;Stark,JoshuaM;VanAmburg,JosephC;Woodall,KaylenK;VanBeusecum,JustinP;Agrawal,Vineet;Smart,CharlesD;Pitzer,Ash
通讯作者：
Pitzer,Ash

Transpulmonary generation of cell-free hemoglobin contributes to vascular dysfunction in pulmonary arterial hypertension via dysregulated clearance mechanisms.

DOI：
10.1002/pul2.12185
发表时间：
2023-01
期刊：
PULMONARY CIRCULATION
影响因子：
2.6
作者：
Meegan, Jamie E.;Kerchberger, Vern Eric;Fortune, Niki L.;McNeil, Joel Brennan;Bastarache, Julie A.;Austin, Eric D.;Ware, Lorraine B.;Hemnes, Anna R.;Brittain, Evan L.
通讯作者：
Brittain, Evan L.

Cell-Free Hemoglobin Increases Leukocyte Adhesion and Mitochondrial Oxidative Damage in the Pulmonary Microvascular Endothelium.

无细胞血红蛋白增加肺微血管内皮中的白细胞粘附和线粒体氧化损伤。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Riedmann,KyleJ;Conger,AdrienneK;Meegan,JamieE;Ware,LorraineB;Bastarache,JulieA
通讯作者：
Bastarache,JulieA