This proposal comprises a 4-year plan to prepare Kenneth E. Remy, MD, MHSc. for independence as a physician-scientist studying the influence of dysregulated plasma heme metabolism upon alterations to host immunity and to develop mechanistic therapies for this problem. Dr. Remy?s previous work at the National Institutes of Health and currently at Washington University serve as the basis for this proposal. Washington University School of Medicine is an exemplary location for Dr. Remy to develop his research platform in hematology-immunology, as there is a longstanding history of NIH funded research and breadth of resources available. Additionally, there is significant crosstalk among departments (Dr. Remy?s mentors across two different departments) and with other institutions including the NIH, Harvard University, and Columbia University (Dr. Remy?s proposed advisory panel). Dr. Remy?s immediate goal is to fulfill the aims outlined in this proposal. Sepsis is an invasive infectious disease associated with dysregulated systemic inflammation and more than 4 million deaths worldwide per annum. Specific targeted therapies are lacking. Many of these patients (~50%) receive a red blood cell (RBC) transfusion as supportive therapy. Recent evidence indicates that RBC transfusions may further disrupt a patient?s immune system and lead to worse outcomes. This disruption may be causally linked to release of free heme from the RBC transfusion, by altering evolution of host immune phenotype in response to infection. This project will focus on pediatric sepsis with the following three specific aims: ? Aim 1: Determine the effect of RBC transfusion during sepsis on heme processing in plasma. ? Aim 2: Characterize the effect of plasma heme on monocyte immune phenotype. ? Aim 3: Elucidate the effect of plasma heme on toll-like receptor 4 (TLR4) - and HO-1-based monocyte signaling. The knowledge gained from successfully achieving these aims will help define the impacts and clinical consequences of RBC transfusion on plasma heme metabolism and immune function in sepsis and, more generally, in other critical illnesses. This knowledge is crucial so that Dr. Remy?s laboratory can translate these to development of mechanistic therapies that may improve sepsis outcomes.
This K08 career development award proposal describes the training and skills that the PI, Dr. Kenneth Remy, will require over the next 4 years to become an independent physician-scientist with expertise pertaining to the investigation of heme dysregulation of the innate immune system in patients with sepsis. This proposal will explore a causal relationship between dysregulated plasma heme metabolism in pediatric sepsis after RBC transfusion and altered innate immunity (via TLR4 binding or co-stimulation), which exacerbates inflammation and worsens outcome. Collectively, the proposed experiments will provide key insights for a current gap in knowledge that will contribute to our understanding of how RBC transfusion directly modulates the immune system and contributes to morbidity and mortality in patients with sepsis.
