Red blood cell modifiers for Plasmodium falciparum growth in sickle cell disease erythrocytes

Sickle cell disease (SCD) is a deadly red blood cell (RBC) disorder estimated to affect over 300,000 newborns annually. In SCD, mutated hemoglobin (HbS) polymerizes and causes RBCs to become sickle- shaped. SCD remains prevalent because heterozygous carriers (HbAS) are partially resistance to Plasmodium falciparum malaria, which causes 400,000 deaths annually. HbS polymerization in low oxygen (O2) as the main driver in HbAS resistance to P. falciparum has recently been identified. This should suggest homozygous HbSS confers greater resistance to malaria, but paradoxically, infected SCD individuals (HbSS) have increased malaria morbidity and mortality. This research proposes 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. 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. Archer’s prior research experiences have allowed her to acquire the cellular biology skills to investigate in vitro malaria growth. Through the critical mentored K08 award, she is 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, her primary institution, has a distinguished record of training young physician-scientists for leadership roles in pediatric hematology research. She has assembled an excellent scientific advisory committee, consisting of Drs. Higgins, Goldberg, and Sankaran. Drs. Brugnara and Nathan, will continue to serve as her career mentors and guide her research and training experiences. With the structured mentoring, educational, and research plans detailed in this proposal, she will acquire the necessary expertise to become a successful independent investigator with a focus on hemoglobinopathies and malaria.

Project details

Modeling

Aug 2020 — Apr 2025

$505,320

United States