Grant: $309,952 - Department of Health and Human Services - Jun. 3, 2009
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Award Description: The response of macrophages to infectious microorganisms is enhanced by interferon (IFN) gamma through gene expression modulation, which results in an increased ability to respond to infection. We have shown that the local production of IFNgamma in the heart, mediated by invariant NKT cells, protects mice during infection with Borrelia burgdorferi (Bb), the causative agent of Lyme disease. Our preliminary data also show that a mechanism that mediates the action of IFN? in macrophages is through the repression of expression of methylation-controlled J protein (MCJ), a member of the DnaJ protein family of cochaperones. MCJ loss of expression has been implicated in the resistance of cancer cells to chemotherapeutic drugs. However, its physiological function, especially in innate immune cells is unknown. Our preliminary data show for the first time, that MCJ is a negative regulator of macrophage responses to Bb. Our central hypothesis is that the cochaperone MCJ negatively regulates the expression of CD1d by macrophages and the production of IFNgamma by iNKT cells that infiltrate the infected heart, affecting the regulatory loop of macrophage activation. As a corollary, we propose that IFN? protects against Lyme carditis by repressing the expression of MCJ in macrophages. To test this hypothesis we intend to assess the modulation of Lyme carditis and the local immune response in mice that lack MCJ; as well as the specific contribution of macrophage MCJ; and address the regulation of macrophage responses by MCJ, including their capacity to present antigens to iNKT cells. These studies will provide evidence of the contribution of the IFNgamma target, MCJ to the response of macrophages to infectious agents and the identification of potential targets of therapeutic intervention.
Project Description: During the first quarter of the award, we have started the work proposed in the application (see above for the abstract). In particular, we have obtained the MCJ-deficient mice and started a breeding colony. We have aslo started experiments to assess the function of invariant NKT cells. We have initially begun to isolate iNKT cells to perform experiments in vitro by cell sorting and also we have performed a pilot study to address the stimulation of these cells in response to the prototypic antigen alpha GalCer. The results obtained so far are very preliminary. Personnel in place: the PI; a Graduate student; and one Postdoctoral Fellow. Further, a second postdoctoral fellow is currently being selected to complete the personnel associated with the project.
Jobs Summary: 2 Research Assts (Total jobs reported: 1)
Project Status: Less Than 50% Completed
This award's data was last updated on Jun. 3, 2009. Help expand these official descriptions using the wiki below.