甲状旁腺素相关肽核定位序列与C末端通过抑制氧化应激和DNA损伤发挥延缓衰老的作用机制研究

The deficiency of the nuclear localization sequence (NLS) and C terminus of parathyroid hormone related peptide (PTHrP) mice (i.e.,PTHrP KI mice) exhibit premature senescence phenotype， but the molecular mechanism is unclear.To investigate whether the premature senescence occurred in PTHrP KI mice is associated with oxidative stress and DNA damage, Parameters related to oxidative stress and DNA damage will be examined in PTHrP KI and their wild-type (WT) littermates to determine whether PTHrP NLS and C terminus deficiency will lead to increased oxidative stress and DNA damage; PTHrP KI mice will be treated with antioxidant, N-acetylcysteine (NAC) or vehicle, the phenotypes will be analyzed using techniques of histopathology, cellular and molecular biology to determine whether NAC treatment can ameliorate the premature senescence phenotypes in PTHrP KI mice; Chk2 gene will be deleted in PTHrP KI mice to generate Chk2 knockout and PTHrP KI double mutant mice and compared each other and to their wild-type littermates to determine whether the deletion of Chk2 gene can rescue the premature senescence phenotypes occurred in PTHrP KI mice by blocking DNA damage response pathway. This study will be helpful to reveal the anti-senescence mechanism of PTHrP NLS and C terminus and will provide theoretical and experimental evidence to develop PTHrP NLS and C terminus as a drug to against senescence.

甲状旁腺素相关肽(PTHrP)核定位序列(NLS)与C末端缺失小鼠(即PTHrP KI小鼠)呈现早衰表型，但分子机制不明。为了研究其早衰是否与氧化应激和DNA损伤有关，通过比较PTHrP KI和同窝野生型小鼠的氧化应激和DNA损伤相关指标的变化，以明确PTHrP NLS和C末端缺失是否引起氧化应激和DNA损伤增加；通过用抗氧化剂(NAC)处理PTHrP KI小鼠，运用组织病理学、细胞和分子生物学方法分析NAC处理组与对照组PTHrP KI小鼠表型差异，明确NAC处理能否改善其早衰表型；通过在PTHrP KI小鼠敲除Chk2基因，建立PTHrP和Chk2双基因突变小鼠,比较分析它们与PTHrP KI小鼠表型差异，明确阻断DNA损伤反应通路能否改善PTHrP KI小鼠早衰表型。本研究将有助于揭示PTHrP NLS和C末端在抗衰老中的作用机制，为将其开发成抗衰老药物提供理论和实验基础。