Anti-oxidant Promoting Cytokine LIF Enhances Neural Cell Survival During Ischemia

描述（由申请人提供）：细胞因子，白血病抑制因子（LIF），已被证明是神经系统疾病，包括中风的潜在治疗分子。虽然LIF已被证明可以激活细胞存活途径，但其确切机制尚未阐明。我们的实验室已经证明，LIF保护培养的少突胶质细胞（OLs）免受氧葡萄糖剥夺（OGD）。其机制之一是通过增加抗氧化酶金属硫蛋白-3 （Mt3）和过氧化物还原素-4 （Prdx4）的表达来减少细胞外氧化应激。本实验将阐明导致Mt3和Prdx4表达增加以减少氧化应激的LIF信号传导机制。我们的假设是，LIF通过抗氧化信号保护暴露于缺血条件下的少突胶质细胞。该建议将利用体外缺血模型来确定负责的信号通路

DESCRIPTION (provided by applicant): The cytokine, leukemia inhibitory factor (LIF), has been shown to be a potential therapeutic molecule for neurological disorders, including stroke. While LIF has been shown to activate cellular survival pathways, exact mechanisms have yet to be elucidated. Our laboratory has shown that LIF protects cultured oligodendrocytes (OLs) from oxygen glucose deprivation (OGD). One of its mechanisms is by increasing the expression of antioxidant enzymes, metallothinein-3 (Mt3) and peroxiredoxin-4 (Prdx4), to reduce extracellular oxidative stress. The proposed experiments will elucidate the LIF signaling mechanisms leading to the increased expression of the Mt3 and Prdx4 to reduce oxidative stress. Our hypothesis is that LIF protects oligodendrocytes exposed to ischemic conditions via antioxidant signaling. This proposal will utilize an in vitro model of ischemia to define the signaling pathway responsible for the protective and antioxidant effects of LIF. Moreover, we will expand on these results to determine in vivo whether delayed i.v. administration of LIF protects OLs in the rat brain from focal cerebral ischemia through increased antioxidant activity. Lastly we will test this delayed administration for its efficacy to enhance long-term behavioral recovery. This proposal will provide the data for additional animal studies to examine LIF as a potential therapeutic to widen the treatment window for stroke.