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

项目摘要 这个R35应用程序描述了一个强大的研究框架，以促进发现和翻译新的 急性呼吸窘迫综合征（ARDS）是急性呼吸道疾病的常见原因， 失败，死亡率高，没有有益的靶向治疗。ARDS仍然是一个重要的 健康问题每年影响19万美国人，造成数十亿美元的损失，并使大多数美国人 患者死亡或严重受损。需要对发病机制有新的认识，以加深我们的认识。 了解导致ARDS的潜在机制以及开发新的治疗方法。 因此，存在未满足的需要，以定义可以研究的临床相关治疗靶点。 通过稳健的临床前研究机械地且快速地进行。在过去的14年里， 把我的研究团队建设成处于转化发现的前沿。我的小组已经取得了重大进展 有助于理解ARDS病理生理学。我实验室的主要工作是定义 肺泡毛细血管屏障功能和功能障碍的细胞和分子调节剂，是ARDS的基础 病理我的R35研究项目旨在使用肺组织识别ARDS中的新介质 成像质谱和单细胞水平的基因表达谱的深度表型分析 用先进的统计方法来识别主要目标。新靶点将在体外转基因中研究 模型系统来定义细胞和分子机制，以促进新的 在临床前模型中测试的治疗剂。我的研究框架集中在三个目标上：发现， 机制与翻译目标1 -发现。为了实现这一目标，我们将利用 成像质谱和单细胞RNA测序，以创建表达谱和蛋白质“图谱” 受伤和未受伤的人的肺。利用先进的统计方法，我们将确定有前途的 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， 机构资源和新的方法，我们将定义基本的病理机制，导致 通过产生新的转基因细胞和小鼠系， 机械研究。目标3 -翻译。基于我们现有的离体人肺和体内小鼠 模型，我们将根据我们发现的新靶点生成严格的临床前数据， 机制研究。有了这个R35，我的实验室将通过以下方式推进NHLBI的使命： 急性损伤和未损伤人的单细胞转录谱和组织蛋白表达水平 肺，确定新的治疗目标，在ARDS，定义细胞和分子机制， 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。R35 将提供必要的支持和灵活性，让我在ARDS方面取得新的突破。

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.