Project: Research project

Project Details


DESCRIPTION: (Adapted from investigator's abstract) Nitric oxide (NO) is
the principal mediator of many of the cytokine-inducible macrophage
activities during a cell-mediated immune response, including the killing of
infectious pathogens and tumor cells. However, elevated levels of NO have
been associated with a number of common chronic inflammatory diseases such
as diabetes, rheumatoid arthritis, asthma and inflammatory bowel disease.
Thus, regulation of NO synthesis by activated macrophages is critical to
maintaining a balance between an effective immune response and
tissue-damaging inflammation and cell death. This balance is achieved by a
complex interplay between positive and negative effectors of macrophage
activation. Macrophage-stimulating protein, the ligand for the STK receptor
tyrosine kinase, suppresses NO production by IFN-gamma-activated macrophages
in vitro. Subsequently, mice lacking the STK receptor exhibit increased
inflammation, tissue damage and death following the onset of a cell-mediated
immune response. The proposed studies will explore the mechanism by which
the STK receptor regulates macrophage activation and NO production using a
combination of biological, biochemical and genetic analyses. First,
IFN-gamma-activated macrophages from the STK knockout mice will be used to
further examine the effect the absence of the STK receptor has on the
activation of macrophages both in vitro and in vivo. Second, macrophage
cell lines expressing the STK receptor will be generated in order to study
the signaling properties of STK in the context of macrophage activation, and
the mechanism by which it alters the response of these cells to IFN-gamma.
Finally, the STK deficient mice will be crossed with knockouts of other
known regulators of macrophage activation, starting with the interferon
gamma receptor, as well as mice lacking inducible nitric oxide synthase
(iNOS). Macrophages from these mice will be studied to determine which
signals lie in the same pathway, and how these signals intersect. By
understanding, in more detail, the regulation of macrophage activation, the
PI hopes to begin to identify targets for suppression of the tissue-damaging
effects of inflammation without compromising the host immune response.
Effective start/end date7/1/986/30/03