This is an application for a K23 award for Dr. Katherine Dobbs, a Pediatric Infectious Diseases specialist at Case Western Reserve University School of Medicine. Dr. Dobbs is establishing herself as a young investigator in translational, patient-oriented research of pediatric malaria. This K23 award will provide Dr. Dobbs with the support necessary to achieve the following goals: 1) to obtain rigorous training in epigenetics laboratory techniques; 2) to acquire advanced skills in biostatistics and epigenetics analyses by obtaining a Masters in Biostatistics on a Genomics and Bioinformatics Track; 3) to become an expert in translational, patient-oriented research on the innate immune response to malaria infection; 4) to develop the technical and leadership skills needed to lead an interdisciplinary research team; and 5) to secure independent R01-level funding. Dr. Dobbs has assembled an experienced, multidisciplinary mentoring team comprised of her primary mentor, Dr. James Kazura, an expert in malaria immunology, genetics, and epidemiology; and 3 co-mentors: Dr. Arlene Dent, a Pediatric Infectious Diseases specialist with expertise in malaria immunology in young children and pregnant women; Dr. Douglas Golenbock, a leader in research on innate immunity, epigenetics, and infectious diseases; and Dr. Dana Crawford, an expert in bioinformatics and genetic epidemiology. The mechanisms underlying the development of immunity to malaria remain poorly understood. Dr. Dobbs will study regulation of monocyte functions in Kenyan children during acute uncomplicated malaria and 2 weeks, 6 weeks, and 6 months following treatment using samples collected as part of larger prospective observational cohort studies in western Kenya. This project will focus on changes in the monocyte epigenome that underlie changes in monocyte function during acute malaria in children (Aim 1) and on the molecular mechanisms that lead to impaired monocyte phagocytic function during acute malaria (Aim 2).
In Aim 1, Dr. Dobbs will analyze the epigenetic landscape of monocytes from children during acute malaria compared to 2 weeks, 6 weeks, and 6 months following treatment and compared to age-matched healthy controls.
In Aim 2, Dr. Dobbs will determine the mechanisms responsible for impaired monocyte phagocytosis by analyzing gene and cell surface expression of activating vs. inhibitory receptors (and their downstream signaling pathways) in monocytes from children during acute malaria and 6 weeks after treatment. This research will form the basis of a prospective observational cohort study on innate immune training and human malaria pathogenesis that will be proposed in an R01 application in the final year of the K23 award.
Children in sub-Saharan Africa bear the largest burden of malaria morbidity and mortality. Better understanding of the epigenetic control mechanisms that regulate monocyte functions will inform the rational development of adjunctive therapies aimed at reducing malaria morbidity and mortality in malaria endemic populations.