Project Details
Description
DESCRIPTION ( applicant's abstract) This is an amended application to competitively renew support for a project entitled Molecular Mechanisms in Multiple Organ Dysfunction. The broad, long-term objective of this project is to unravel the mechanisms which regulate the transition from health, through physiologically compensated illness, to physiologically decompensated critical illness. The focus of the work done in the applicant's laboratory has been on stress responses as triggers of apoptosis. In this cycle of the project, a new hypothesis is being proposed, namely that errant physiologic iron primes tissues to undergo apoptosis following critical illness, and that heat activation of apoptosis is responsible, in part, for sustained tissue injury and organ dysfunction in MODS. In this context, the applicant has framed three interrelated aims as questions: (1) What is the role of iron in generating reactive oxygen species (ROS) in post-injury apoptosis? What form does the iron take? What are the roles of the reactive oxygen species and reactive nitrogen intermediates (RNIs)? (2) Where in the network of molecules regulating progression to apoptosis the reactive species generated by this iron/heat mechanism act? (3) Given the substantial redundancy in regulatory networks, which (if any) genes are essential to iron-inducible apoptosis? To address these questions, electron spin resonance (ESR) spectroscopy and apoptosis analyses will be used to interrogate both cultured endothelial cells and genetically engineered mice exposed to iron and other stresses.
Status | Finished |
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Effective start/end date | 1/09/94 → 31/03/04 |
Funding
- National Institute of General Medical Sciences: $195,000.00
- National Institute of General Medical Sciences: $195,000.00
- National Institute of General Medical Sciences: $195,000.00
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