TUMOR NECROSIS FACTOR RECEPTOR IN CASPASE NEURONAL DEATH

Massachusetts General Hospital, Boston MA

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Abstract

DESCRIPTION (Adapted From The Applicant's Abstract): 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.