The proposal hopes to determine whether the expression of stress genes play an important role in cell survival following cerebral ischemia. The proposal will focus on the expression of HSP-70 mRNA, which codes for the major inducible 70 kilodalton heat shock protein. In situ hybridization will be used to detect the expression of HSP-70 mRNA following ischemia. A reversible model of focal ischemia in rat brain will be employed. This produces cortical infarction in the territory of the middle cerebral artery.
The specific aims are to: (1) determine the timecourse and regional expression of HSP-70 mRNA following focal ischemia in rat brain using in situ hybridization, and correlate this expression with the regional extent of histological injury; (2) to determine whether prior induction of HSP-70 protects brain tissue against a subsequent period of ischemia; (3) to determine whether a known protectant, hypothermia, alters the expression of HSP-70 following focal ischemia; (4) to determine whether ischemia enhances the expression of other stress-related genes (c-fox, HSP-90, ubiquitin, glucose-regulated protein, ornithine decarboxylase), using in situ hybridization and (5) to determine whether enhanced expression of HSP-70 mRNA is triggered by a decrease in high-energy phosphates and/or an increase in lactate during the ischemic insult.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029331-03
Application #
3416112
Study Section
Neurology A Study Section (NEUA)
Project Start
1991-05-01
Project End
1995-04-30
Budget Start
1993-05-01
Budget End
1994-04-30
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Boros, Gábor; Karikó, Katalin; Muramatsu, Hiromi et al. (2016) Transfection of Human Keratinocytes with Nucleoside-Modified mRNA Encoding CPD-Photolyase to Repair DNA Damage. Methods Mol Biol 1428:219-28
Boros, Gábor; Miko, Edit; Muramatsu, Hiromi et al. (2015) Identification of Cyclobutane Pyrimidine Dimer-Responsive Genes Using UVB-Irradiated Human Keratinocytes Transfected with In Vitro-Synthesized Photolyase mRNA. PLoS One 10:e0131141
Boros, Gábor; Miko, Edit; Muramatsu, Hiromi et al. (2013) Transfection of pseudouridine-modified mRNA encoding CPD-photolyase leads to repair of DNA damage in human keratinocytes: a new approach with future therapeutic potential. J Photochem Photobiol B 129:93-9
Karikó, Katalin; Muramatsu, Hiromi; Keller, Jason M et al. (2012) Increased erythropoiesis in mice injected with submicrogram quantities of pseudouridine-containing mRNA encoding erythropoietin. Mol Ther 20:948-53
Sansing, Lauren H; Harris, Tajie H; Welsh, Frank A et al. (2011) Toll-like receptor 4 contributes to poor outcome after intracerebral hemorrhage. Ann Neurol 70:646-56
Sansing, Lauren H; Kasner, Scott E; McCullough, Louise et al. (2011) Autologous blood injection to model spontaneous intracerebral hemorrhage in mice. J Vis Exp :
Anderson, Bart R; Muramatsu, Hiromi; Jha, Babal K et al. (2011) Nucleoside modifications in RNA limit activation of 2'-5'-oligoadenylate synthetase and increase resistance to cleavage by RNase L. Nucleic Acids Res 39:9329-38
Kariko, Katalin; Muramatsu, Hiromi; Welsh, Frank A et al. (2008) Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther 16:1833-40
Muramatsu, Hiromi; Welsh, Frank A; Kariko, Katalin (2006) Cerebral preconditioning using cortical application of hypertonic salt solutions: upregulation of mRNAs encoding inhibitors of inflammation. Brain Res 1097:31-8
Muramatsu, Hiromi; Kariko, Katalin; Welsh, Frank A (2004) Induction of tolerance to focal ischemia in rat brain: dissociation between cortical lesioning and spreading depression. J Cereb Blood Flow Metab 24:1167-71

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