Projects and Grants per year
Grants and Contracts Details
Description
The overall goal of this PPG is to evaluate the hypothesis that calpain inhibition represents a viable
therapeutic target for intervention following traumatic brain injury (TBI). TBI represents a leading cause of
death and disability in adults and children, and improved treatment options are urgently needed. Calpains
are excessively activated following TBI and are strongly implicated in the secondary neuronal degeneration.
The resultant hypothesis is that calpain inhibition will protect against the pathological and functional
consequences of TBI. Although straightforward, this hypothesis has proven to be surprisingly difficult to
evaluate. A handful of studies in animal models of TBI have demonstrated improved neurological recovery
and attenuated axonal injury with calpain inhibitor treatment. However, evidence that these benefits are
directly related to calpain inhibition has been elusive. Moreover, there are numerous unanswered questions
regarding the mechanisms by which calpains contribute to cell death and dysfunction. This PPG brings
together investigators with strong expertise in calpain biochemistry and in animal models of TBI to evaluate
three distinct mechanisms of calpain inhibition following TBI. Project 1 explores the role of the endogenous,
specific, and potent calpain inhibitor, calpastatin, in modulating calpain function and improving outcome
following TBI. Project 2 is translational and will investigate the ability of new small molecule calpain inhibitors
to attenuate the pathological and functional consequences of TBI. Project 3 will examine the roles of
individual calpain isoforms in neurodegeneration and TBI, focusing on the hypothesis that IJ-calpain is a
pathologic isoform and is localized to mitochondria. In addition to the three projects, there will be three cores:
A, Administrative and Biostatistical Core; B, Animal Core; and C, Proteomics and Biomarker Core. Together,
these projects and cores will provide a clear indication as to whether calpain inhibition represents a viable
therapeutic target for TBI, and whether the small molecule calpain inhibitors are suitable for subsequent
preclinical and clinical investigation.
Status | Finished |
---|---|
Effective start/end date | 5/1/07 → 4/30/10 |
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Projects
- 1 Finished
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Calpain as a Therapeutic Target for TBI (P01)
Geddes, J., Guttmann, R., Hall, E., Kryscio, R. & Saatman, K.
National Institute of Neurological Disorders & Stroke
5/1/07 → 4/30/10
Project: Research project