PROJECT SUMMARY/ABSTRACT Sickle cell disease (SCD) is a deadly red blood cell (RBC) disorder estimated to affect over 300,000 newborns annually1. In SCD, mutated hemoglobin (HbS) polymerizes2 and causes RBCs to become sickle- shaped. SCD remains prevalent because heterozygous carriers (HbAS) are partially resistance to Plasmodium falciparum malaria3,4, which causes 400,000 deaths annually5. I recently identified HbS polymerization in low oxygen (O2) as the main driver in HbAS resistance to P. falciparum6. This should suggest homozygous HbSS confers greater resistance to malaria, but paradoxically, infected SCD individuals (HbSS) have increased malaria morbidity and mortality7-9. I propose a novel hypothetical model of SCD and malaria interaction in which RBC factors, like fetal hemoglobin (HbF), that create a RBC reservoir in which little to no HbS polymerization occurs, may enable severe malaria. Using a variety of SCD RBC cell types, I will map and model the in vitro growth dynamics of P. falciparum in SCD erythrocytes and identify RBC factors that influence malaria infectivity within this population. This work is foundational in elucidating the molecular mechanisms underlying the interaction between SCD and malaria, and is a major first step in identifying novel treatment targets for severe malaria, SCD, and its comorbidities. I am a pediatric hematologist co-mentored by Dr. Manoj Duraisingh and Dr. Caroline Buckee, both of Harvard's T.H. Chan School of Public Health. My long-term goal is to become an independent physician- scientist investigating the effect of the RBC host on malaria growth and to target such factors therapeutically. My prior research experiences have allowed me to acquire the cellular biology skills to investigate in vitro malaria growth. Through the critical mentored K08 award, I am now well positioned to acquire new skills in mathematical modeling and parasite genetics to better understand the epidemiology of hemoglobinopathies in malaria endemic regions, assess the impact of the introduction of RBC polymorphisms within communities, and find potential therapeutic targets for children with SCD that become infected with malaria. The Boston Children's Hospital and Harvard T.H. Chan School of Public Health are internationally recognized research programs with a number of expert researchers in the areas of hemoglobinopathies, mathematical modeling, and malaria. Boston Children's Hospital, my primary institution, has a distinguished record of training young physician-scientists for leadership roles in pediatric hematology research. I have assembled an excellent scientific advisory committee, consisting of Drs. Higgins, Goldberg, and Sankaran. Drs. Brugnara and Nathan, will continue to serve as my career mentors and guide my research and training experiences. With the structured mentoring, educational, and research plans detailed in this proposal, I will acquire the necessary expertise to become a successful independent investigator with a focus on hemoglobinopathies and malaria.

PROJECT NARRATIVE Despite significant improvements in the control and treatment of malaria infections in many parts of Africa, children with sickle cell disease (SCD) remain particularly vulnerable to fatal infections, a phenomenon that remains poorly understood. Fetal hemoglobin (HbF) and other red blood cell (RBC) factors influence SCD pathology and, by their effects on sickle hemoglobin (HbS) polymerization, may also affect malaria parasitemia and virulence. This research proposal aims to understand P. falciparum growth in SCD, including the SCD RBC host factors that either protect against or worsen severe malaria infection, and identify potential therapeutic targets for individuals with co-morbid SCD.