The overall goal of this project is to develop an understanding of the genetic basis for host resistance and susceptibility to tuberculosis (TB). The disease remains the largest cause of death in the world from a single infectious disease, and the largest attributable cause of death from AIDS in developing countries. Preliminary data indicate that resistance and susceptibility to experimental TB in the genetically and immunologically well studied mouse model is multigenic, and the aim is to identify multigenic factors and their interactions that control host resistance and susceptibility to TB.
The specific aims are: 1) to identify loci of the murine genome that control susceptibility or resistance to infection with M. tuberculosis using principally two genetic approaches: classical linkage analysis (intercrossing and backcrossing), and use of a unique set of recombinant congenic inbred mouse strains (RCS) that have a defined 6-12 percent of their genome contributed by the donor parent strain; 2) to genetically map the resistance and susceptibility genes with sufficient precision (1cM resolution) and efficiency, through use of the RCS and from them production of Interval Specific Congenic Strains, to rapidly permit positional cloning; 3) to clone and sequence the major resistance and susceptibility genes and to create transgenic knockouts to learn, where possible, how the genes and the pathways they control contribute to resistance or susceptibility; 4) to identify measurable immunological and physiological functions and correlates of the genes controlling host resistance or susceptibility to tuberculosis; and 5) to ascertain, in collaborative studies, whether human genes or pathways homologous to those identified in mouse are associated with resistance or susceptibility of human populations to clinical tuberculosis.
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