This application for the Mentored Quantitative Research Career Development Award requests funding to support Dr. Elebeoba E. May, a computational scientist, to receive training in the molecular aspects of infectious diseases and to participate in a mentored research program focused on understanding the genetic basis of Mycobacterium tuberculosis latency and reactivation. This career development proposal consists of an overlapping didactic and research phase. The majority of Dr. May's didactic phase will occur during the first three years. This developmental phase is designed to provide significant training in the biology of infectious diseases with an emphasis on tuberculosis as a model organism. The coursework, seminars, and workshops will provide the biological background that will enable Dr. May to successfully implement the proposed research. Dr. May will gradually move into the research phase, compiling data the first two years and then increasing research activities from year three through year five. The research objective is to quantitatively identify, model and analyze genetic networks, metabolic networks, and immune response pathways that are involved in the Mtb latency and reactivation process.
Specific aims and steps for accomplishing the research objective include: 1) Determine host-Mtb gene expression during a murine model of Mtb infection and subsequent development of latency; 2) Develop a quantitative model of Mtb and host during infection relating gene-level expression to metabolic pathways, and metabolic pathways to cellular immune response; 3) For a given microarray expression profile, simulate and quantify host-pathogen interactions for Mtb-mouse immune response during latency and reactivation. The quantitative models developed will be used to perform virtual Mtb knockout experiments to identify genes that influence latency and reactivation. In vivo anti-sense knockout experiments will be performed to validate whether the genes identified by the quantitative model impact latency and reactivation. Successful completion of this program will provide Dr. May with the training necessary to successfully develop and conduct independent research programs in biomedicine and infectious diseases. This work will also augment current understanding of latency and reactivation in Mtb, a pathogen that causes significant morbidity worldwide.
