The Role of Sirt1 in Neonatal Hypoxic Ischemic Brain Injury

描述（由申请人提供）：脑供血和供氧受阻导致的中风，可因缺氧缺血（HI）导致神经元死亡。人类新生儿对大脑的缺氧缺血性损伤通常是围产期窒息的结果，这些损伤的幸存者可能受到多种临床问题的困扰，包括脑瘫、癫痫发作、运动障碍和脑病。由HI引起的神经元损失的相当大一部分是凋亡途径激活的结果。Sirti是酵母NAD+依赖性蛋白脱乙酰基酶Sir2的哺乳动物直向同源物，已被证明部分通过抑制细胞凋亡来调节对多种细胞应激的抗性。在轴突变性和神经退行性疾病的背景下，Sirti也与神经元存活有关。我建议调查是否Sirti介导细胞耐缺氧缺血，特别是在新生儿。为了检验这一点，将评估大脑中Sirti缺陷或过表达的小鼠对新生儿缺氧缺血性损伤的敏感性。此外，Sirti保护免受此类损伤的分子机制也将被研究。

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.