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

• 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
• 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

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.

项目摘要 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）的治疗靶标，这是急性呼吸系统的常见原因 失败的死亡率高，没有有益的靶向疗法。 ARDS仍然很重要 健康问题每年影响19万美国人，耗资数十亿美元，而大多数 患者死亡或严重受损。需要对发病机理的新见解来加深我们 了解导致ARDS和开发新疗法的基本机制。 这是一个未满足的需要定义可以研究的临床相关治疗靶标 机械和迅速通过强大的临床前研究进行。在过去的14年中，我一直 建立我的研究团队成为转化发现的最前沿。我的小组做了专业 对了解ARDS病理生理学的贡献。我实验室的主要重点是定义钥匙 肺泡毛细管屏障功能和功能障碍的细胞和分子调节剂，这些功能和功能障碍是ARDS的基础 病理。我的R35研究计划旨在使用肺组织识别ARDS中的新型介体 成像质谱和基因表达谱的深层表型在单细胞水平上耦合 采用先进的统计方法来识别领先的目标。新靶标将在体外转基因研究 定义细胞和分子机制的模型系统，以促进新颖的发展 将在临床前模型中测试的治疗。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 成像质谱和单细胞RNA测序以创建表达曲线和蛋白质“ MAP” 使用高级统计方法，我们将确定承诺 靶向进一步研究的目标。目标2 - 机制。利用我们现有的肺损伤模型， 机构资源和新方法，我们将定义领导的基本病理机制 通过产生新型的转基因细胞和小鼠系的肺泡毛细管屏障渗透性 机械研究。目标3 - 翻译。建立我们现有的离体人体肺和体内鼠标 模型，我们将根据我们的发现和发现中确定的新目标生成严格的临床前数据 机理研究。使用此R35，我的实验室将通过：生成一个目录的NHLBI任务 急性损伤和未受伤的人类的单细胞转录谱和组织蛋白表达水平 肺，识别ARDS中的新型热靶标，定义了调节的细胞和分子机制 肺泡毛细管屏障功能障碍和在小鼠和人类模型中进行临床前研究。 R35 将为我提供在ARDS中打破新地面所需的支持和灵活性。