Evolution and resolution of ARDS molecular phenotypes

ARDS 分子表型的进化和解析

基本信息

批准号：
10592022
负责人：
Aartik Sarma
金额：
$ 18.87万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-05 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592022
关键词：
Acute Respiratory Distress Syndrome Airway Disease Automobile Driving Biological Biological Markers Biology COVID-19 patient COVID-19/ARDS Candida Cell Proliferation Cell model Clinical Complement Complex Computer Analysis Data Disease Enterobacteriaceae Epidemiologic Methods Evolution Family Foundations Future Gene Expression Gene Expression Profiling Genes Genomic approach Goals Grant Health Care Costs Immune Inflammation Inflammatory Interferons Interleukin-1 Interleukin-4 Knowledge Learning Liquid substance Longitudinal Studies Lower respiratory tract structure Lung Lung diseases Macrophage Mechanical ventilation Medicine Mentored Patient-Oriented Research Career Development Award Mentorship Methods Morbidity - disease rate National Heart, Lung, and Blood Institute Pathway Analysis Pathway interactions Patient Recruitments Patients Phenotype Plasma Positive-Pressure Respiration Pre-Clinical Model Precision therapeutics Pulmonary Inflammation Randomized, Controlled Trials Reporting Research Research Personnel Resolution Respiratory System Risk STAT6 gene Sampling Signal Transduction Simvastatin T-Cell Activation T-Lymphocyte Taxon Testing Time Series Analysis Trachea Training Transforming Growth Factor beta Trauma patient Uncertainty Virulence Factors aspirate bioinformatics tool biological adaptation to stress career development cohort cytokine design dimensional analysis drug candidate dysbiosis experience fungus high dimensionality insight large datasets lung injury metatranscriptome metatranscriptomics microbial microbial community microbiome molecular phenotype mortality novel polarized cell repaired respiratory microbiome response secondary analysis single-cell RNA sequencing skill acquisition skills systemic inflammatory response transcriptome sequencing transcriptomics treatment response ventilation

项目摘要

ABSTRACT. The acute respiratory distress syndrome (ARDS) is associated with high mortality, morbidity, and health care costs (Bellani 2016). Dozens of candidate drugs for ARDS have been identified in preclinical models, but none consistently reduced mortality in randomized controlled trials (RCTs). This dismal record is likely driven in part by the heterogenous biology encompassed within the definition of ARDS (Rubenfeld 2015). Unsupervised clustering of plasma biomarkers and clinical variables recently identified two molecular phenotypes of ARDS (Calfee 2014) which may enable predictive enrichment in future RCTs. Uncertainty about the key biologic mechanisms that distinguish these two phenotypes from each other remains a critical knowledge gap. The overall objective of this proposal is to recruit patients to an established cohort of mechanically ventilated patients and identify distinct mechanisms of lung injury in ARDS molecular phenotypes. The central hypothesis of this proposal is that ARDS phenotypes are driven by different dysregulated pathways that result in distinct clinical trajectories and responses to treatment. In Aim 1, I will use single cell RNA sequencing to study tracheal aspirates and develop a model of cell signaling in the lung of each molecular phenotype. I hypothesize hyperinflammatory ARDS is associated with increased Type 1 T-cell polarization and a diminished response to interferons in macrophages. In Aim 2, I will use metatranscriptomic sequencing to characterize differences in the tracheal aspirate microbiome in each phenotype. I hypothesize TA metatranscriptomes will have distinct microbial community composition in each phenotype, which will be characterized by increased burden of enteric bacteria in the hypoinflammatory phenotype and an increased burden of fungi in the hyperinflammatory phenotype. In Aim 3, I will collect longitudinal tracheal aspirate and plasma samples to study the evolution of pro-inflammatory, pro-resolution, and pro-fibrotic pathways in each ARDS phenotype. I hypothesize ARDS phenotypes have distinct trajectories of inflammation and repair pathways in the first week of mechanical ventilation. I will address a critical gap in knowledge required to develop phenotype-specific precision treatments. This K23 award is sponsored by Dr. Carolyn Calfee, an experienced ARDS researcher whose group has pioneered analyses of ARDS molecular phenotypes, and Dr. Stephanie Christenson, a computational biologist with expertise in the transcriptomics of airway diseases. Their mentorship and the research and training plan in this K23 will support my continued career development and allow me to learn essential skills I require to be an independent investigator, including advanced computational analyses, epidemiological methods, and management of a research cohort. Developing these skills will be essential to achieve my long-term goal of understanding the mechanistic pathways distinguishing ARDS phenotypes to identify novel potential therapies. The proposed aims lay the foundation for a R01 proposal to study the interaction of pulmonary and systemic inflammation in ARDS phenotypes.

抽象的。急性呼吸窘迫综合征 (ARDS) 与高死亡率、发病率和医疗保健费用（Bellani 2016）。临床前已确定了数十种 ARDS 候选药物模型，但在随机对照试验（RCT）中没有一个模型能够持续降低死亡率。这个惨淡的记录是可能部分是由 ARDS 定义中包含的异质生物学驱动的（Rubenfeld 2015）。血浆生物标志物和临床变量的无监督聚类最近确定了两个分子 ARDS 的表型（Calfee 2014）可能有助于未来 RCT 的预测丰富。不确定性区分这两种表型的关键生物学机制仍然是一个关键知识差距。该提案的总体目标是将患者招募到已建立的队列中机械通气患者并确定 ARDS 分子中肺损伤的不同机制表型。该提案的中心假设是 ARDS 表型是由不同的驱动因素失调的途径导致不同的临床轨迹和对治疗的反应。在目标 1 中，我将使用单细胞 RNA 测序研究气管抽吸物并开发肺部细胞信号传导模型每个分子表型。我假设高炎症 ARDS 与 1 型 T 细胞增加有关极化和巨噬细胞对干扰素的反应减弱。在目标 2 中，我将使用元转录组学测序以表征每种表型的气管抽吸物微生物组的差异。我假设 TA 宏转录组在每个表型中将具有不同的微生物群落组成，这将是其特征是低炎症表型中肠道细菌负担增加，并且高炎症表型中真菌的负担。在目标 3 中，我将收集纵向气管抽吸物并血浆样本来研究每个细胞中促炎症、促消退和促纤维化途径的演变 ARDS 表型。我假设 ARDS 表型具有不同的炎症和修复轨迹机械通气第一周的通路。我将解决所需知识的关键差距开发表型特异性的精准治疗。该 K23 奖项由 Carolyn Calfee 博士赞助，她是经验丰富的 ARDS 研究人员，其团队率先分析了 ARDS 分子表型，Dr. Stephanie Christenson 是一位计算生物学家，在气道疾病转录组学方面拥有丰富的专业知识。他们的指导以及本次 K23 中的研究和培训计划将支持我持续的职业发展并让我学习成为一名独立调查员所需的基本技能，包括高级技能计算分析、流行病学方法和研究队列管理。开发这些技能对于实现我的长期目标至关重要，即理解区分机制的途径 ARDS 表型以确定新的潜在疗法。拟议的目标为 R01 奠定了基础建议研究 ARDS 表型中肺部和全身炎症的相互作用。