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Project Title:
Molecular Mechanisms in TBI: Bench to Bedside Project 3 INOS and TBI
Funding Agency:
NIH/Neurological Institute
Total Project Period:
May 11, 2000 - Feb 28, 2005
Principal Investigator:
Patrick Kochanek, MD
Co-Investigator(s):
Timothy Carlos, Hong Yan, Valerian Kagen, Simon Watkins
Project Summary:
Inducible nitric oxide synthase (iNOS) is a NOS isoform that was initially speculated to play an important role in traumatic brain injury (TBI). The hypothesis of this proposal is that iNOS is expressed after TBI and is a powerful endogenous neuroprotectant.
Specific aims are as follows: 1. Determine the time course, magnitude, and cellular localization of iNOS induction after experimental TBI in both rats and mice. 2. Test whether iNOS is an endogenous neuroprotectant and improves both histopathological and functional outcome after TBI, using both iNOS inhibitors in rats and mice and iNOS KO mice. 3. Test in both rats and mice if overexpression of iNOS by gene transfer with an adenovirus-based vector is neuroprotective after TBI. 4. Determine in our rat and mouse models how iNOS confers its neuroprotective effects, including evaluation of downstream markers such as cykokines, nerve growth factor (NGF) and posttraumatic cerebral blood flow. 5. Define, in humans with severe TBI, the global and local production of NO, as assessed by nitrite and nitrate levels in cerebrospinal fluid (CSF) and brain interstitial fluid, respectively, and determine the time course, magnitude, and cellular localization of iNOS induction in human cerebral contusions. |
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