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：
9894231
负责人：
Julie Anne Bastarache
金额：
$ 43.18万
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/9894231
关键词：
Acute Acute respiratory failure Adult Respiratory Distress Syndrome Affect Alveolar American Biological Models Blood capillaries Catalogs Cells Clinical Data Clinical Trials Coupled Death Rate Development Disease Expression Profiling Functional disorder Future Gene Expression Genetic Transcription Goals Health Human Image Impairment In Vitro Laboratories Lead Life Lung Maps Mass Spectrum Analysis Mediator of activation protein 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 Tissue imaging Tissues Transgenic Model Transgenic Organisms Translating Translational Research Translations base clinically relevant cost design flexibility human model in vivo injured innovation insight lung injury 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.

项目概要该 R35 应用程序描述了一个强大的研究框架，以促进新发现和翻译急性呼吸窘迫综合征 (ARDS) 的治疗目标，这是急性呼吸道疾病的常见原因死亡率高且没有有益的靶向治疗的失败仍然是一个重要的问题。健康问题每年影响 19 万美国人，造成数十亿美元的损失，并使大多数人患者死亡或严重受损需要对发病机制有新的认识来加深我们的研究。了解导致 ARDS 的潜在机制并开发新的治疗方法。因此，定义可研究的临床相关治疗靶点的需求尚未得到满足在过去的 14 年里，我一直在机械地、快速地进行强有力的临床前研究。使我的研究团队处于转化发现的前沿，我的团队取得了重大进展。对理解 ARDS 病理生理学的贡献我实验室的主要重点是定义关键。 ARDS 的肺泡毛细血管屏障功能和功能障碍的细胞和分子调节剂我的 R35 研究计划旨在利用肺组织识别 ARDS 中的新型介质。成像质谱法和单细胞水平基因表达谱的深度表型分析相结合利用先进的统计方法来确定主要靶标，将在体外转基因中研究新靶标。定义细胞和分子机制的模型系统，以促进新型药物的开发我的研究框架以三个目标为中心：发现、机制和翻译。目标 1 – 发现为了实现这一目标，我们将使用新的突破。成像质谱和单细胞 RNA 测序创建表达谱和蛋白质“图谱” 使用先进的统计方法，我们将确定有希望的人类肺部。目标是进一步研究目标 2——利用我们现有的肺损伤模型。机构资源和新方法，我们将定义导致的基本病理机制通过生成新的转基因细胞和小鼠系来改善 ARDS 中的肺泡毛细血管屏障通透性目标 3——基于我们现有的离体人类肺和体内小鼠的翻译。模型，我们将根据我们的发现和研究中确定的新目标生成严格的临床前数据通过这个 R35 机制研究，我的实验室将通过以下方式推进 NHLBI 的使命：生成一个目录。急性损伤和未损伤人类的单细胞转录谱和组织蛋白表达水平肺，确定 ARDS 的新治疗靶点，定义调节的细胞和分子机制肺泡毛细血管屏障功能障碍并在小鼠和人类模型中进行临床前研究。将为我在 ARDS 领域开辟新天地提供必要的支持和灵活性。