Acute damage to the central nervous system caused by stroke or trauma is the most frequent neurologic cause of death and disability. We hypothesize that the responses to these types of injury share common mechanisms that can serve as the basis for new therapeutic approaches. Since August 1990, when this program began, we have been cooperating in an effort to develop new types of therapies. The common theme we have been pursuing concerns the effects of neurotropic factors in models of central nervous system injury. At a cellular level, the impacts of stroke and traumatic injuries are similar. Both cause death and degeneration of some neurons and this is followed by reactive tissue changes. These reactions include sprouting of remaining neurons, and new growth of the supporting structures including glia and blood vessels. A class of substances known to respond to tissue damage in other parts of the body is growth factors (which include neurotrophic factors in the brain). These factors seem an especially important group since they are apparently required for the survival and maintenance of various types of neurons. Our ultimate goals are to develop methods of therapy that are likely to be more effective than prevailing techniques. Using animal models of central nervous system ischemia and trauma, we intend to: 1) determine the sequence of some critical events, at a biochemical level, occurring during the early phases of traumatic or ischemic injury, and 2) evaluate the effects of several types of neurotrophic factors and other related molecules in preventing damage and restoring function. We anticipate these studies will give us insights into the natural responses of the central nervous system to acute damage. These investigations will help us learn to augment the reparative processes, and inhibit dysfunctional responses. This will provide a scientific basis for selecting treatments. Some of these therapies should prevent or minimize neurologic damage at the time of injury. Other treatments have the potential to restore function to areas in which irreversible damage has already occurred.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS028121-05
Application #
2266771
Study Section
Special Emphasis Panel (SRC (02))
Project Start
1990-08-01
Project End
1999-05-31
Budget Start
1995-07-20
Budget End
1996-05-31
Support Year
5
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Maher, Pamela (2014) Proteasome Assay in Cell Lysates. Bio Protoc 4:
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Brennand, Kristen J; Gage, Fred H (2011) Concise review: the promise of human induced pluripotent stem cell-based studies of schizophrenia. Stem Cells 29:1915-22
Maher, Pamela (2008) Proteasome inhibitors prevent oxidative stress-induced nerve cell death by a novel mechanism. Biochem Pharmacol 75:1994-2006
Maher, Pamela (2008) The flavonoid fisetin promotes nerve cell survival from trophic factor withdrawal by enhancement of proteasome activity. Arch Biochem Biophys 476:139-44
Maher, Pamela; Salgado, Karmen F; Zivin, Justin A et al. (2007) A novel approach to screening for new neuroprotective compounds for the treatment of stroke. Brain Res 1173:117-25
Shackelford, Deborah A; Yeh, Richard Y (2006) Modulation of ERK and JNK activity by transient forebrain ischemia in rats. J Neurosci Res 83:476-88
Shackelford, Deborah A (2006) DNA end joining activity is reduced in Alzheimer's disease. Neurobiol Aging 27:596-605
Lapchak, Paul A (2006) Memantine, an uncompetitive low affinity NMDA open-channel antagonist improves clinical rating scores in a multiple infarct embolic stroke model in rabbits. Brain Res 1088:141-7

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