Dr. Jason Rose is resubmitting this application for a Mentored Research Career Development Award entitled ?Discovering and Developing Recombinant Molecular Scavenging Agents for the Treatment of Carbon Monoxide (CO) Induced Cardiovascular Dysfunction?. Dr. Rose is a pulmonary and critical care physician, and now, Assistant Professor of Medicine at the University of Pittsburgh seeking additional training in molecular engineering, mitochondrial biology, animal models of disease, and drug discovery to further develop into an independent research investigator. His long-term goal is to lead large academic drug design, discovery and development programs. His short-term training goals, for this proposal, are to: (1) acquire proficiency in the assessment of cardiovascular pathophysiology in animal models of disease and develop the skillset to become a primary investigator in studying the role of mitochondrial dysfunction in human disease; (2) gain expertise in molecular engineering, targeted drug design and drug discovery assay development; and (3) develop the management skills to become an expert in the early-stage development of new therapeutics. Building on his recent graduation from the Tepper School of Business MBA program, he will supplement his training with didactic courses in molecular pharmacology, drug discovery and cardiovascular physiology. He has assembled experts in drug discovery, cardiovascular dynamics, and mitochondrial biology to form a cohesive mentor team and scientific advisory committee. The proposed work will be conducted within the Division of Pulmonary, Allergy, and Critical Care at the University of Pittsburgh, which has a strong history of training physician scientists and provides a superb infrastructure for his research and his path to academic independence. CO exposure is the leading cause of poisoning in the world and there is no antidote to CO. Current interventions have limited effectiveness: new therapies are needed. The central objective of this proposal is to further identify and develop an antidotal therapy for CO poisoning.
Aim 1 will focus on establishing the mechanisms of CO- induced cardiovascular toxicity: investigating CO-induced mitochondrial inhibition and measuring hemodynamics in a severe CO poisoning mouse model.
Aim 2 will test the efficacy and safety of recombinant neuroglobin to reverse the molecular and cardiac dysfunction caused by CO toxicity.
Aim 3 will seek to identify novel heme containing molecules as CO scavengers, using a new manufacturing process and discovery assays. Although this proposal is ambitious, Dr. Rose has now completed his MBA degree during his intense clinical and research training demonstrating his ability to multitask in the academic environment. The combination of (1) formal training in cardiovascular physiology, innovation and molecular pharmacology; (2) novel research experience that includes disease modeling, drug development and discovery elements; (3) an experienced, diverse mentorship team and advisory committee; and (4) the strong institutional environment at the University of Pittsburgh will equip Dr. Rose for a career as an independent research investigator and academic drug discovery leader.
There are 50,000 Carbon monoxide (CO) poisoning cases every year in the United States, with many survivors suffering cardiac dysfunction, which is associated with increased long-term mortality. Our lab has developed a CO scavenging agent, recombinant Neuroglobin (rNgb) that directly binds CO from poisoned mitochondria, reversing a major cause of CO pathophysiology and morbidity. The current study will: 1) investigate the basis of the cardiovascular toxicity of CO poisoning; 2) demonstrate the efficacy and safety of a rNgb antidotal therapy and 3) design and develop a second generation CO scavenging based upon a synthetic heme molecule containing peptide.
