Fas (CD95) is of principal importance to normal functioning of the immune system, as evidenced by the marked dysregulation of autoreactive B cells and accompanying autoantibody formation that characterize Fas-deficient animals. The sensitivity of B cells to Fas-mediated apoptosis is regulated by specific receptor signals, in which surface immunoglobulin engagement, and IL-4R engagement, produce a state of Fas-resistance. Modulation of susceptibility to Fas killing suggests a system that protects B cells during critical interactions with FasL-bearing, activated T cells, but that can contribute to the survival of autoreactive B cells when activated inappropriately.
F AIM i s a completely novel, evolutionarily conserved gene product that is induced by stimuli that produce Fas-resistance and that functions as a Fas Apoptosis Inhibitory Molecule. The broad, long term objective of this work is to understand the role of inducible Fas-resistance in B cell homeostasis, and immune activity. The specific goal is to determine the means by which FAIM produces Fas-resistance and the consequences of FAIM-induced Fas-resistance for serological autoreactivity and immune responsiveness. This will be accomplished through 3 specific aims. 1. Determine the point at which Fas-triggered signaling for B cell death is interrupted by FAIM, by assessing the activation and activity of specific caspases, monitoring pre-caspase events in the Fas pathway, and immunoprecipitating a FAIM-associated protein. 2. Identify the regions and residues of FAIM responsible for Fas-resistance, by truncating and mutating faim and correlating structural changes with anti-apoptotic function. 3. Evaluate the role of FAIM in directing autoreactive B cell dysfunction by producing FAIM-overexpressing transgenic mice combined with screening for autoantibody formation and evaluation of mixed bone marrow chimeras, and by examining mice that overexpress both FAIM and Bcl-XL, and that express FAIM on an MRL background. Because FAIM has no substantial regions of homology with any other defined sequence, the studies described herein are expected to identify a novel mammalian motif and strategy for regulating Fas-induced cell death, which may then become a target for therapeutic manipulation to enhance desired immune responses, such as anti- tumor immunity, and to diminish unwanted immune responses, such as autoimmune dyscrasias.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045112-02
Application #
6362407
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Deckhut Augustine, Alison M
Project Start
2000-03-01
Project End
2004-02-29
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
2
Fiscal Year
2001
Total Cost
$289,293
Indirect Cost
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
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