Falciparum malaria remains a grave threat to global health despite recent gains in malaria control. Field studies and laboratory investigations have greatly expanded the understanding of malaria pathogenesis, but these findings have not been fully translated into an integrated understanding of malaria pathophysiology that can leverage molecular models for clinical benefit. Because malaria control measures are at risk of failure due to parasite evolution and changes in immunity, sustaining the gains made in malaria control will require a new generation of therapeutic and preventive malaria measures that are based on a sound understanding of malaria pathogenesis. The focus of the proposed investigations is the exploration of the family of P. falciparum var virulence genes that encode the P. falciparum erythrocyte membrane protein 1 (PfEMP1). Lines of evidence drawn from both laboratory and clinical studies implicate PfEMP1 as a major effector of both pathogenicity and immunogenicity. Because the interaction of parasite pathogenesis and host immunity produces malaria clinical morbidity of great heterogeneity, a better understanding of the mechanisms of PfEMP1 evolution and its functional role in clinical infections can suggest means by which to alter the balance of the host-parasite interaction and reduce morbidity. The projects in this proposal seek to answer three basic questions of parasite pathogenesis: 1) How do P. falciparum populations generate diverse repertoires of PfEMP1 variants that enable immune escape and produce parasite pathogenic phenotypes?; 2) Does the natural resistance to infection conferred by hemoglobin C - which disrupts PfEMP1 morphology and abrogates pathogenicity in vitro - translate to a mediation of the expression of PfEMP1 in clinical infections?; and 3) How do specific PfEMP1 transcripts in severe malaria states correlate with measures of parasite cytoadherence phenotypes and adaptive immune response? In the short-term, these projects are intended to both answer these fundamental questions of P. falciparum virulence as well as provide opportunities for a junior investigator train in the investigation of microbial pathogenesi. The candidate has extensive experience with clinical medicine, clinical epidemiology, and molecular epidemiology, and proposes to use these investigations of parasite virulence as a means to transition to a career in malaria pathogenesis. The candidate will work under a mentor who is well-established in the malaria field and with a broad range of expertise. The investigations will be carried out in a leading epidemiology department in the Gillings School of Global Public Health, providing a rich environment of researchers working with diverse pathogens, across diverse disciplines, and in many malaria-endemic countries. The research proposed will provide hands-on training in genetic analyses that will be supplemented by more formal workshops and advanced courses in parasitology, genomic epidemiology, and experimental genetics. Career development will be augmented outside of the laboratory by two mechanisms: 1) participation in formal research planning seminars for junior faculty at UNC to assist in establishing independent research programs, and 2) guidance from a Scientific Advisory Committee of more senior investigators in microbial pathogenesis and genomics from UNC, Duke University, and NIAID. Clinical critical thinking skills will be maintained by a unique arrangement by contract with Duke, which testifies to the commitment to the candidate's career success from two independent institutions. Ultimately, research independence will be established by financial independence, and the mentor is committed to this. Two avenues of obtaining extramural support will be utilized: 1) pilot funding for junior investigators from both he Gillings School and UNC, and 2) leveraging the data generated in the proposed investigations into applications for a variety of field and laboratory-based R-series NIH grants. Ultimately, this K-08 career development award will produce an independent investigator in translational malaria pathogenesis. Success in achieving this goal is mediated by 1) the candidate's previous training and commitment to academic research, 2) the mentor's track record of success in malaria genetics and in training mentees, 3) the institutional commitment to the candidate and its cross-disciplinary environment, and 4) complementary career development opportunities and laboratory investigations that provide a bridge to translational studies of malaria virulence The long term goals of both the investigator and this field of investigation are to develop a more integrated understanding of malaria pathogenesis that can serve as a foundation for new therapeutics, preventive measures, and, ultimately, vaccine strategies.