Stroke is the third most common cause of death in the United States with approximately 175,000 fatalities each year. Programmed cell death or apoptosis plays an important role in neuronal injury occurring during and after stroke. The understanding of these mechanisms may offer therapeutic strategies. Activation of the tumor necrosis factor receptor (TNFR) family, including the Fas and TNFalpha receptors, has been shown in nonneuronal cells as an important mechanism in caspase-mediated apoptosis. Although the ligands TNFalpha and FasL have recently been found in the central nervous system (CNS), it is not clear whether their corresponding receptors are expressed during cerebral ischemia. The objective is to determine whether the Fas and TNFalpha receptors play a role in apoptosis during cerebral ischemia using in vivo models in rodent and in vitro neuronal cell culture models. To achieve this goal the following questions will be investigated: 1) Is the expression of the Fas and TNF receptors induced in the CNS under ischemia?; 2) In which CNS cell types are these receptors expressed?; and 3) Is the caspase cascade, including activation of caspase 8, involved in Fas/TNFalpha receptor-mediated neuronal apoptosis. The techniques which will be employed to address these questions include reversed transcription polymerase chain reaction (RT-PCR), in situ hybridization, immunoblotting, fluorescent in situ transcription (FIST), and immunohistochemistry applied to CNS cell cultures combined with cerebral ischemia models in the rodent.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS002162-03
Application #
6539501
Study Section
NST-2 Subcommittee (NST)
Program Officer
Nunn, Michael
Project Start
2000-06-28
Project End
2004-04-30
Budget Start
2002-05-01
Budget End
2004-04-30
Support Year
3
Fiscal Year
2002
Total Cost
$113,751
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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Plesnila, N; Zinkel, S; Le, D A et al. (2001) BID mediates neuronal cell death after oxygen/ glucose deprivation and focal cerebral ischemia. Proc Natl Acad Sci U S A 98:15318-23