PTHrP NLS与C末端促进小鼠脊髓损伤后髓鞘再生的作用及机制研究

项目名称： PTHrP NLS与C末端促进小鼠脊髓损伤后髓鞘再生的作用及机制研究

项目编号： No.81472081

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张永杰

作者单位： 南京医科大学

项目金额： 61万元

中文摘要： 我们前期研究发现甲状旁腺素相关肽（PTHrP）核定位（NLS）与C末端缺失小鼠（即PTHrP KI小鼠）少突胶质前体细胞（OPCs）增殖分化降低，凋亡增加，髓鞘发育障碍；且OPCs氧化应激反应增强，DNA损伤加剧，但具体机制不清。为明确PTHrP NLS与C末端缺失是否可通过增强氧化应激，加剧DNA损伤，进而激活ATM、ATR通路, 抑制PI3K/AKT/mTOR通路，从而抑制OPCs增殖分化、促进其凋亡，首先，我们利用PTHrP KI小鼠，结合体内外实验，研究PTHrP NLS与C末端缺失对OPCs的影响是否由氧化应激与DNA损伤反应所介导；然后，运用PTHrP87-139蛋白处理脊髓损伤小鼠，观察其能否通过减轻OPCs的氧化应激与DNA损伤反应而促进髓鞘的功能性再生。本研究有望阐明PTHrP NLS与C末端调控OPCs发育的机制，并为促进脊髓损伤修复提供新的治疗靶标。

中文关键词： 脊髓损伤；髓鞘再生；少突胶质前体细胞；甲状旁腺素相关肽；氧化应激

英文摘要： Our previous studies have shown that the deficiency of the nuclear localization sequence (NLS) and C terminus of parathyroid hormone related peptide (PTHrP) mice (i.e., PTHrP KI mice) exhibit the decrese of proliferation and differentiation , increase of apoptosis of oligodendrocyte progenitor cells (OPCs), resulting in the deficiency of myelinogenesis. Meanwhile, the oxidative stress and DNA damage is increased in OPCs from the PTHrP KI mice, but the mechanism of which is still not clear. To identify whether the deficiency of PTHrP NLS and C terminus may inhibit the proliferation and differentiation, and increase the apoptosis of OPCs by increase the oxidative stress and DNA damage to the OPCs via activation of ATM and ATR signal pathways and inhibition of PIK3/AKT/mTOR signal pathway, we design this study as following: firstly, PTHrP KI mice will be used to identify whether the deficiency of PTHrP NLS and C teriminus will suppress the development of OPCs through the activation of oxidative stress and DNA damage response (DDR) pathway. Secondly, PTHrP87-139 peptide will be constructed and used to treat the injuried spinal cord in adult mice to verify whether PTHrP87-139 peptide can promote the axonal remyelination after spinal cord injury (SCI) via decrease the oxidative stress and DDR. This study will be helpful to further reveal the role of PTHrP NLS and C terminus in the regulation of OPCs development and will provide the experimental evidence to develop the PTHrP 87-139 peptide as a drug to promote axonal remyelination after SCI.

英文关键词： spinal cord injury;remyelination;oligodendrocyte progenitor cells;PTHrP;oxidative stress