2020 IARS Mentored Research Award
Catharina Conrad, MD, PhD
University of California, San Francisco
San Francisco, CA
Dr. Conrad’s Research
Protease Profiling for Rapid Phenotyping and Monitoring of ARDS
Acute respiratory distress syndrome (ARDS) is a life-threatening condition of critically ill patients, characterized by excessive lung inflammation and pulmonary edema resulting in lung failure. The Covid19 crisis has exposed a significant weakness of standard care for patients with ARDS, and that is shortcomings in ARDS risk assessment, prevention and treatment. A key to overcome these challenges may be molecular phenotyping to predict prognosis and mortality of ARDS patient subgroups. Several classes of proteases, including serine, cysteine and metalloproteases, are instrumental in the pathogenesis of lung injury and modulate the immune response. This proposal intends to determine real-time protease profiles in lung fluids of ARDS patients as a correlate of inflammation to dynamically track disease progression and develop personalized therapeutic approaches. Our consideration is that the activities of inflammatory mediators predict their biological relevance more precisely than mere expression levels. In Aim 1 of this application we will use fluorescent reporters based on known cleavage sites to detect multiple protease activities (>10) by the change of fluorescence over time. Pilot data suggests that proteolytic signatures of ARDS survivors significantly differ from cleavage patterns of non-survivors within 30 minutes, pointing towards a great potential of protease activities for rapid risk assessment of patients with lung inflammation. In Aim 2 we will attribute the activities to particular proteases derived from specific cell types at different phases of inflammation during the course of ARDS. To validate these proteases as therapeutic targets for ARDS, we will perform genetic and pharmacological in vivo studies to neutralize proteolytic activity in murine models of acute lung injury. In vitro cell-culture models will provide mechanistic insight and complement our mouse studies.
ADAM8 signaling drives neutrophil migration and ARDS severity
Catharina Conrad et al.
Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent, unmet need for improved early recognition and therapeutic development. Neutrophil influx is a hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins (ADAMs). Through this research, the authors propose that in acute inflammatory lung diseases such as pneumonia and ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain.