Welcome to the Cohen Lab

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Research Interests

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The Cohen lab is an NIH, DoD, BARDA and DARPA funded basic and translational science research group, which studies coagulation and inflammation perturbations after injury. Specifically, the lab continues to examine the mechanisms of traumatic coagulopathy and mediators of protein C system activation after trauma. In addition to its basic science focus, the Cohen research group transnationally studies similar topics through multiple clinical characterization and interventional trials aimed at elucidating the post trauma coagulation milieu and optimal resuscitation and treatment. Finally, the Cohen group has an active interest in silico data and model driven approaches to modeling of biological and physiologic systems. In keeping with this, his group has done extensive work on the use of big data, machine learning, and artificial intelligence towards improving personalized medicine and outcomes. This work includes multi scale modeling projects ranging from coagulation and endothelial biology to causal inference prediction of patient physiologic state and trajectory. Taken together, this work seeks to understand the biological and physiological phenotypic milieu after any threat or injury towards the goal of identifying patient phenotypes and trajectories and providing real time dynamic individualized medical countermeasures. Separately our group works actively on surgical performance and wellness.

Active Research Projects

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Activation of Coagulation in Trauma
Trauma when combined with tissue hypoperfusion cause Trauma Induced Coauglopathy and Thromboinflammation. Our group has identified multiple phenotypes of coagulopathies (changes in blood coagulation) and inflammation which are caused by injury and shock and associated with mortality and poor outcomes. Our goals are to identify specific mechanistic drivers of both TIC and Thromboinflammation, and in doing so, identify countermeasures and therapeutics to stop bleeding, balance homeostasis, and save lives. Equally important is to identify longitudinal changes in physiology, protein, metabolite, and RNA expression to identify endotypic and phenotypic patient states to predict patient trajectory and identify targeted personalized treatment to return patients to homeostasis, thereby saving lives and reducing suffering.

The Role of the Protein C System in TIC and Thromboinflammation
The protein C system is a key mechanistic driver of TIC and its associated morbidity and mortality following injury, and due to its distinct dual anticoagulant and cytoprotective activities, APC both drives TIC development and mitigates thromboinflammation. Thus, therapeutics targeting the protein C (PC) pathway could be ideal for trauma patient management. Supported by our preliminary data, we propose that activation of PC after trauma is an acute protective evolutionary response to preserve cellular function following severe injury, with the unfortunate sequalae of this otherwise beneficial response being TIC. This evolutionary protective response to severe injury is considered maladaptive, providing an early 'too much of a good thing' response (cytoprotective AND coagulopathic), which is followed by a late 'too little of a good thing' exhaustion of this response with resultant dysregulated thromboinflammation and organ failure. We propose a dual APC -targeted approach, such that pharmacologic APC-based cytoprotection will help to restore endothelial function and mitigate thromboinflammation of trauma and inhibition of anticoagulant effects and will help to curb bleeding and TIC. We are now positioned to explore innovative pathways for mechanistic studies aimed at developing targeted therapies to selectively modulate the protein C system, thereby preventing bleeding and treating thromboinflammation. In our lab, new activity-selective nanobodies to APC and an engineered factor (F) V variant that bypasses APC anticoagulant activity are studied to counter the coagulopathy of TIC. Further, engineered 3K3A-APC with minimal anticoagulant activity and full cytoprotective activity and novel APC-mimetic cytoprotective PAR1 and PAR3 derived agonist peptides are studied to address thromboinflammation. Mechanistic and therapeutic exploration of these novel compounds are used to address the clinical challenges of TIC and thromboinflammation, thereby improving both short and long-term survival among critically injured patients.

Applied Systems Biology for Traumatic Coagulopathy
We use both model driven and data driven methodologies to achieve the dual purpose of prediction and mechanistic understanding of the post trauma milieu. These systems models are designed facilitate the use of feedback control to mechanistically manipulate the coagulation to control and prevent TIC. We use modeling to employ feedback control and dynamical systems theory so as to intervene at any timepoint, or even at multiple timepoints, in a coagulopathic trajectory. Our approach will permit coagulation factor concentration modulation that is tailored to the trauma patient, thereby realizing personalized and precision medicine for the trauma patient.

Mechanistic Understanding of Thromboinflammation
In keeping with our work on TIC above, our lab studies multiple other components of thromboinflammatory biology. We have extensively published on mitochondrial metabolic dysfunction after trauma, calcium signaling, and endothelial barrier function. Each of these topics represent a large amount of synergistic work which continues in our lab to achieve the overall goal of understanding and achieving thromboinflammatory homeostasis after trauma and shock.

Human Performance
Our group works actively on human performance as it relates to sleep and recovery. Our goal with this work is to detail the drives of and countermeasures to impaired cognitive and physical surgical performance. In doing so we hope to improve non-athletic performance to take better care of ourselves and our patients, thereby dually saving lives.

Publications

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