Molecular Mechanisms in Ischemia The central theme of this program project is that cerebral ischemia alters the expression of gene products that help to determine whether ischemic neurons live or die. The scientific goals are to identify these gene products, and by modifying their expression, to modify the outcome of cerebral ischemia. The rational for this approach is the increasing understanding that cell death, including neuronal death from ischemia, is an active, evolving process that involves new protein synthesis. Identifying gene products that determine the fate of ischemic neurons would have major significance in increasing understanding of the pathophysiology of ischemic neural injury and in pointing the way toward new therapeutic approaches to stroke and related disorders. For example, the discovery that expression of a deleterious gene product is increase in ischemia could lead to treatment aimed at blocking its expression or action, while the finding that a gene produce is neuroprotective in ischemia would prompt efforts to enhance its expression or pharmacologically mimic its effects. The strategy for achieving our objectives is to use state-of-the-art molecular and cellular techniques to identify gene products whose expression is altered in brain regions preferentially sensitive and preferentially resistant to global cerebral ischemia, and in brain rendered tolerant to ischemia by prior exposure to a sub lethal ischemic insult, and in vivo rat models of cerebral ischemia (Project 1). In vitro cell culture models of neuronal ischemia and neuronal cell death will then be used to investigate the functional significance of these gene products, by assessing whether modifying their expression with antisense oligodeoxynucleotides or viral vector-mediated gene transfer also modifies neuronal death (Project 2). The most promising candidate neurocidal and neuroprotective gene products that emerge from Projects 1 and 2 will then be evaluated further by antisense techniques and gene transfer in vivo rat models of cerebral ischemia (Project 3). The Viral Vector Core (Core A) will develop and prepare replication-defective herpes simplex viral vectors for the gene transfer studies proposed in Projects 2 and 3. The Administrative Core (Core B) will provide clerical assistance, meeting arrangements, centralized ordering, grant management, and statistical and scientific consultation through internal and external advisory boards.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Jacobs, Tom P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Simon, Roger P (2016) Epigenetic modulation of gene expression governs the brain's response to injury. Neurosci Lett 625:16-9
Simon, Roger P; Meller, Robert; Zhou, An et al. (2012) Can genes modify stroke outcome and by what mechanisms? Stroke 43:286-91
Stevens, Susan L; Leung, Philberta Y; Vartanian, Keri B et al. (2011) Multiple preconditioning paradigms converge on interferon regulatory factor-dependent signaling to promote tolerance to ischemic brain injury. J Neurosci 31:8456-63
Stapels, Martha; Piper, Chelsea; Yang, Tao et al. (2010) Polycomb group proteins as epigenetic mediators of neuroprotection in ischemic tolerance. Sci Signal 3:ra15
Marsh, B J; Williams-Karnesky, R L; Stenzel-Poore, M P (2009) Toll-like receptor signaling in endogenous neuroprotection and stroke. Neuroscience 158:1007-20
West, G Alexander; Golshani, Kiarash J; Doyle, Kristian P et al. (2009) A new model of cortical stroke in the rhesus macaque. J Cereb Blood Flow Metab 29:1175-86
Khan, Adil A; Mao, Xiao Ou; Banwait, Surita et al. (2008) Regulation of hypoxic neuronal death signaling by neuroglobin. FASEB J 22:1737-47
Pignataro, Giuseppe; Maysami, Samaneh; Studer, Francesca E et al. (2008) Downregulation of hippocampal adenosine kinase after focal ischemia as potential endogenous neuroprotective mechanism. J Cereb Blood Flow Metab 28:17-23
Jin, Kunlin; Mao, Xiao Ou; Xie, Lin et al. (2008) Neuroglobin protects against nitric oxide toxicity. Neurosci Lett 430:135-7
Sato, Yu; Meller, Robert; Yang, Tao et al. (2008) Stereo-selective neuroprotection against stroke with vitamin A derivatives. Brain Res 1241:188-92

Showing the most recent 10 out of 74 publications