Dr. Kathleen Stringer Receives Two Federal Grants Totaling $3.3M to Support Her Research Program
Kathleen A. Stringer, PharmD’85, Professor of Clinical and Translational Pharmacy, Director of the NMR Metabolomics Laboratory and Associate Director of the Michigan Center for Integrative Research in Critical Care (MCIRCC), has been awarded two federal grants totaling nearly $3.3 million.
The Stringer Laboratory is focused on investigating the metabolic consequences of critical illnesses like sepsis, plastic bronchitis and acute respiratory distress syndrome (ARDS). In addition, the group’s interest in inflammatory lung diseases extends to identifying and testing novel therapeutics and furthering understanding of inflammatory processes in the lungs. To date, there are no therapeutic options for these clinically challenging problems, partially because the disease processes are not well understood. To further knowledge of disease processes and drug response, Dr. Stringer’s research program utilizes metabolomics, the measurement of small molecules in biological samples.
The first award is an R01 from the National Institute of General Medical Sciences. It supports a pharmacometabolomics study of L-carnitine in patients with septic shock. This project is a collaborative effort with two of her Michigan colleagues, Dr. Charles Evans of the Michigan Regional Comprehensive Metabolomics Resource Core (MRC)2 and Dr. Alla Karnovsky of the Department of Computational Medicine and Bioinformatics. She will also work with two faculty from the University of Mississippi Medical Center, Dr. Michael Puskarich and Dr. Alan Jones; Dr. Jones serves as the principal investigator on the parent clinical trial. Dr. Stringer will employ metabolomics to assess the utilization of L-carnitine in these severely ill patients. In previous work, the group showed that patients who use carnitine are more likely to survive sepsis. Metabolomics will aid in understanding what metabolic differences exist between those patients who use carnitine and those that do not. This information will aid in further understanding sepsis phenotypes and possibly identify drug target opportunities.
“Sepsis is a leading cause of death in the US and is a very challenging clinical problem,” says Dr. Stringer. “Accurate diagnosis is difficult and presently, there is no effective drug therapy. One of the greatest hurtles to finding drug targets for sepsis is the heterogeneity of these patients,” continues Dr. Stringer. “By using carnitine to probe sepsis metabolism, we expect to better define this heterogeneity which we expect to unveil drug target opportunities.”
The second grant is an US Food and Drug Administration Orphan Drug R01 that will fund a phase II safety and efficacy clinical trial of inhaled tissue plasminogen activator (tPA) for pediatric plastic bronchitis (a very rare pulmonary disease) that includes a significant metabolomics component. “This is the first clinical trial of inhaled tPA and represents a culmination of over 15 years of work that began while I was a faculty member at the University of Colorado” says Dr. Stringer. “Upon arriving at the University of Michigan in 2007, the effort escalated due to the support and collaboration of co-investigator Drs. Regine White (Caruthers), a pediatric cardiology Clinical Pharmacist and Adjunct Clinical Assistant Professor of Pharmacy, and co-principal investigator Kurt Schumacher from Pediatric Cardiology.”
“Initially the work was support by an R15 from the National Institute of Child Health and Human Development. This funding enabled Kristina Brooks, a pharmacy student at the time, to begin the painstaking work of drafting an Investigational New Drug (IND) application. MICHR, in particular, Jeanne Wright and Kevin Weatherwax, was instrumental in getting the IND polished and submitted to the FDA. Actually, Dr. Dan Clauw, was the first at MICHR to hear the story of inhaled tPA and has been a big supporter,” notes Dr. Stringer.
The grant will fund the study at several other clinical sites around the country including the Children’s Hospital of Philadelphia, Cincinnati Children’s, Medical University of South Carolina, and Stanford University. In addition to Dr. Schumacher and Dr. White, Dr. Samya Nasr (Pediatric Pulmonary) and Dr. Jeff Myers (Anatomic Pathology) will join the team at U-M, which will serve as the coordinating center.
As part of the testing of tPA safety and efficacy, metabolomics will be employed to assess drug response and to gain a better understanding of the metabolic disruptions associated with plastic bronchitis. All the participating centers will collect samples for metabolomics assays that will be performed at the NMR Metabolomics Laboratory and the (MRC)2.