The following proposal describes a five-year training program for the development of an academic career in Infectious Diseases. The principal investigator has completed her clinical training in Internal Medicine at Yale New Haven Hospital and Infectious Diseases at New York Presbyterian, Weill Cornell Medical Center. She now aims to develop her research skills studying the molecular biology of the malaria parasite Plasmodium falciparum with the long term goal of establishing an independent research program combining tropical medicine and molecular biology. The principal investigator has developed a customized research proposal integrating molecular biology of DMA repair and the study of tropical medicine. This proposal will further the understanding of antigenic variation in malaria by integrating the study of the parasite mechanisms for DNA recombination and repair and the genetic analysis of field isolates. Dr. Kirk Deitsch will serve as sponsor and is a leader in the genetic manipulations of P. falciparum. This program is enhanced by the co-sponsorship of Dr. William Holloman, his expertise in DNA recombination and repair enhances both the proposed work and the training of the principal investigator. Research will focus on the var genes that encode PfEMPI, the primary surface protein implicated in antigenic variation of P. falciparum. This surface protein also determines the cytoadherent properties of an infected red cell, a known virulence factor in P. falciparum infection. Surveys of clinical samples have shown that var genes are extremely diverse genetically. Each parasite isolate contains a complement of -60 var genes that is unique, thus giving each parasite its own distinct repertoire of antigenic molecules. How this extreme diversity is generated has not been extensively explored and is the focus of this research proposal. Transgenic parasite lines will be used to directly study different mechanisms of DNA recombination and repair in P. falciparum. Our transgenic parasite lines have been designed so that we can target DNA damage for repair analysis to var gene coding regions or drug selectable markers driven by var gene promoters. In this way, we will be able to study how DNA damage and subsequent repair may contribute to the generation of diversity in this important gene family. The study of var gene changes in field samples will complement our data generated from the study of transgenic parasites. Relevance: Appreciation of the mechanisms that generates diversity in this key parasite surface protein is fundamental to understanding the pathogenesis of P. falciparum infections. Further investigation of the host immune response to malaria infection and how the parasite is able to adapt to this response is important in directing intervention efforts, ie vaccines, and findings ways reduce the burden of malaria worldwide.
|Heinberg, Adina; Kirkman, Laura (2015) The molecular basis of antifolate resistance in Plasmodium falciparum: looking beyond point mutations. Ann N Y Acad Sci 1342:10-8|
|KÃ¼mpornsin, Krittikorn; Modchang, Charin; Heinberg, Adina et al. (2014) Origin of robustness in generating drug-resistant malaria parasites. Mol Biol Evol 31:1649-60|
|Kirkman, Laura A; Lawrence, Elizabeth A; Deitsch, Kirk W (2014) Malaria parasites utilize both homologous recombination and alternative end joining pathways to maintain genome integrity. Nucleic Acids Res 42:370-9|
|Heinberg, Adina; Siu, Edwin; Stern, Chaya et al. (2013) Direct evidence for the adaptive role of copy number variation on antifolate susceptibility in Plasmodium falciparum. Mol Microbiol 88:702-12|
|Kirkman, Laura A; Deitsch, Kirk W (2012) Antigenic variation and the generation of diversity in malaria parasites. Curr Opin Microbiol 15:456-62|