Macrophage Activation by Metabolic and Pathogen Stresses Disorders
Principal Investigator: Mason Freeman
As the main effector arm of the innate immune system,
the macrophage has developed an arsenal of weapons to combat microbial
and non-microbial pathogens. The macrophage accomplishes its task, in
part, by deploying a group of pattern recognition receptors that recognize
common structural motifs present on the surface of the cell walls of microbes.
Some of these motifs appear to be present on self tissues undergoing
apoptosis; however their recognition does not usually induce the dramatic
response triggered by microbial contact. Thus, the macrophage has evolved
receptor and signal transduction pathways that allow it to distinguish
phagocytic activities that need to be accomplished with a minimum of
(e.g., tissue remodeling) from those that must evoke a robust, multicellular
inflammatory response (e.g, clearance of microbial pathogens). The overall
process of an inflammatory reaction is depicted graphically in
With certain stimuli, the process can go awry, either through over-activation
in the acute stages (e.g., septic shock following Gram negative bacteremia)
or via the failure to resolve over time (e.g., the chronic inflammation
of atherosclerosis. One of the central premises of this project is that
the macrophage, when engaged by a pro-inflammatory stimulus, has a relatively
limited repertoire of responses that it can activate. It is our view that
the commonalties of these responses to pathogens, whether microbial or
non-microbial, are likely to be substantial and that they account for
the similarities in the clinical manifestations of a diverse group of
diseases. The over-riding goal of this project is to try to characterize
this repertoire of responses in macrophages using high throughput genomic
and proteomic technologies.
- To perform comparative gene expression studies assessing
the impact of key proteins in inflammatory and stress response pathways,
using macrophages taken from wild type and knock-out mice.
- To explore concordances between murine and human macrophage
expression, and to establish baseline profiles revealing the consequences
of various sample collection practices.
- To analyze gene expression in aortas
taken from normal and apo E null mice and from coronary arteries of
mice following allogeneic heart transplantation.
- To conduct parallel investigations on the gene expression
profiles of human carotid endarterectomy, coronary endarterectomy, and
heart transplant specimens, and to establish, if possible, the characteristic
gene clustering features of these conditions.
To learn more about the Macrophage Activation by Metabolic and Pathogen Stresses Disorders project, visit the Freeman Lab Web Site.