Abstract

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.

  Funding Agency

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

  Institution

Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

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

Showing the most recent 10 out of 28 publications