Project: Research project

Project Details


DESCRIPTION (Adapted from the Investigator's abstract): Apoptosis of
inflammatory leukocytes is widely thought to be crucial for the regulation
of inflammatory responses. The direct investigation of this idea has been
hampered by the inability to demonstrate regulatory molecules specific to
these cells that might permit experimental manipulation of the apoptotic
response. We have isolated and described such a candidate molecule, a Bcl-2
related anti-apoptotic protein named A1. A1 is rapidly induced in
macrophages by pro-inflammatory mediators, and is strongly up-regulated
during acute pathogenic inflammation in mice. The objective of this project
is to clarify the functional roles of A1 in the regulation of cell death
processes during the progress and resolution of inflammatory responses. The
application proposes a model for apoptotic regulation in the acute response
to a pathogen is divided into two stages. In stage one, the innate immune
response generates effector molecules such as nitric oxide that are vital
for host defense but are also pro-apoptotic for macrophages. At this stage,
A1 expression protects the macrophage and permits the inflammatory response
to continue. In stage two, pathogen has been largely cleared, and
inflammatory macrophages are now removed by a second wave of pro-apoptotic
stimuli. This second wave, which may be derived from activated T-cells, is
able to override the protective effects of A1. The Specific Aims will test
and refine this idea will focus on the following three hypotheses: (1)
Mediators of host defense include both 'A1-sensitive' and 'A1-resistant'
apoptotic stimuli. (2) During the acute response to T. gondii infection, a
shift occurs in the inflammatory environment from A1-mediated protection of
macrophages to A1-resistant macrophage apoptosis. (3) Protection of
macrophages during inflammation is mediated by A1 and is vital for host
Effective start/end date6/1/984/30/02


  • Cell Biology
  • Microbiology


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