The Role of Sirt1 in Neonatal Hypoxic Ischemic Brain Injury

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DESCRIPTION (provided by applicant): Stroke, resulting from the blockage of blood supply and oxygen to the brain, can cause neuronal death due to hypoxia ischemia (HI). Human neonatal hypoxic -ischemic injury to the brain is often a result of perinatal asphyxia, and survivors of these insults can be plagued with multiple clinical problems including cerebral palsy, seizures, motor impairment and encephalopathy. A substantial portion or the neuronal loss resulting from HI is a result of activation of the apoptotic pathway. Sirti, the mammalian orthologue of the yeast NAD+depenedent protein deacetylase, Sir2, has proven to regulate resistance to a variety of cellular stresses, in part by inhibiting apoptosis. Sirti has also been connected with neuronal survival, in the context of axon degeneration and neurodegenerative disease. I propose to investigate whether Sirti mediates cell resistance from hypoxia ischemia, specifically in the neonate. To examine this, mice deficient or overexpressing Sirti in the brain will be assessed for their sensitivity to neonatal hypoxic-ischemic injury. In addition, the molecular mechanisms by which Sirti protects from such injuries will be investigated.