Steven H. Graham, Ph.D. M.D.
Professor, Neurology- Ph.D. University of Texas (1982)
- M.D. University of Texas Medical School (1984)
- Office: S-517 Biomedical Science Tower
- Telephone:412-648-3299
- Fax:412-648-3321
- E-mail: sgra@pitt.edu
- Website:
Neuronal cell death in ischemia and trauma.
Research Summary:
Dr. Graham’s laboratory studies how gene expression and activity control cell death in neurons subjected to anoxia, ischemia, and other insults. There are currently two major areas of concentration: programmed cell death and cyclooxygenase-2.
Programmed cell death is the mechanism by which neurons die during normal development and other cells are eliminated via a physiologic cell death process in adult animals. Under pathologic situations such as ischemia, these mechanisms may be reactivated in a maladaptive fashion. There is a plethora of pathways by which programmed cell death may be initiated and executed in mammalian cells. The broad overall objective of our studies is to determine which of these pathways may be important in mediating neuronal cell death in the adult animal. Current investigations focus on the role of bcl-2 family genes and the Fas membrane receptor in mediating ischemic neuronal death.
A second area of concentration is the role of cyclooxygenase-2, the inducible form of the enzyme that catalyzes the production of prostaglandins from arachidonic acid, in neuronal cell death. The pathologic role of cyclooxygenase is best characterized in inflammation where prostaglandins have numerous effects on vasomotor tone, blood flow, blood brain barrier permeability and chemotaxis. However, our laboratory has found that cyclooxygenase-2 activity exacerbates neuronal death secondary to anoxia in primary neuronal culture, where vascular inflammatory effects are eliminated. Current studies are aimed at investigating the mechanisms by which cyclooxygenase-2 activity injure neurons. These results are of interest because specific cyclooxygenase-2 inhibitors have already been developed for arthritis that are very well tolerated drugs. Furthermore, there is epidemiological evidence that cyclooxygenase inhibitors such as Motrin decrease the incidence of Alzheimer’s disease. Thus, the cyclooxygenase-2 activity may be important in the pathogenesis of stroke and neurodegenerative diseases.
Projects for graduate students are available that address both these topics. Techniques utilized in the lab range from primary neuronal tissue cultures to whole animal experiments involving transgenic mice. Gene transcription and expression is assayed via a variety of techniques including PCR, in situ hybridization, Western blots, and immunocytochemistry. Adenoassociated viral vectors are used to alter expression of genes in vivo and in vitro.
Selected Publications:
Jin, K., Nagayama, T., Mao, X., Kawaguchi, K., Hickey, R.W., Greenberg, D.A., Simon, R.P., and Graham, S.H. Two caspase-2 transcripts are expressed in rat hippocampus after global cerebral ischemia. J Neurochem 81:25-35, 2002.