PTHrP核定位序列与C末端调控牙和颌骨发育的作用机制研究

项目名称： PTHrP核定位序列与C末端调控牙和颌骨发育的作用机制研究

项目编号： No.81200755

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 孙雯

作者单位： 南京医科大学

项目金额： 23万元

中文摘要： 我们前期研究发现，甲状旁腺素相关肽(PTHrP)核定位序列(NLS)与C末端缺失(PTHrP KI)小鼠牙和颌骨生长发育存在严重障碍，但机制不明确。为了研究PTHrP NLS和C-末端是否经Gli2介导，抑制p27表达，刺激细胞增殖，促进牙和颌骨的生长发育，将构建PTHrP KI / p27双基因突变小鼠，分析其与单基因突变小鼠的表型差异；使用Gli2基因沉默的颌突外胚间充质干细胞(EMSCs)，给予PTHrP87-139 (即PTHrP NLS和C-末端)处理，检测细胞增殖能力的改变；利用PTHrP87-139对PTHrP KI小鼠及其EMSCs进行干预，观察PTHrP87-139能否纠正PTHrP KI小鼠牙和颌骨的生长发育障碍。本研究有望阐明PTHrP NLS和C-末端在调控牙和颌骨发育中的作用机制，并为PTHrP87-139在临床应用于促进牙和颌骨的生长发育提供理论和实验依据。

中文关键词： 甲状旁腺素相关肽；核定位序列；p27；牙；颌骨

英文摘要： Our previous study found that Parathyroid hormone related protein （PTHrP） nuclear localization sequence (NLS) and C-terminus deficient (PTHrP KI) mice displayed severe defects in dental and mandibular development, but the mechanism is unclear. To investigate whether PTHrP NLS and C-terminus, via Gli2, inhibit p27 expression, stimulate cell proliferation and promote dental and mandibular development, we will delete p27 gene in PTHrP KI mice and their phenotypes will be compared in teeth and mandible with those of p27 deficient, PTHrP KI and wild-type mice. Gli2 siRNAs expressing ectomesenchymal cells will be treated with recombinant mouse PTHrP87-139 to examine whether Gli2 mediate its stimulating role in cell proliferation. PTHrP KI mice or ectomesenchymal cells isolated from PTHrP KI mice will be treated with the PTHrP87-139 to assess whether the treatment of PTHrP87-139 could rescue severe defects in dental and mandibular development occurred in PTHrP KI mice. Results from this study will be helpful to elucidate the mechanism of PTHrP NLS and C-terminus in regulating dental and mandibular development and will provide theoretical and experimental basis for the applications of PTHrP87-139 in clinical study on promoting dental and mandibular development.

英文关键词： Parathyroid hormone related protein；Nuclear localization sequence；p27；Teeth；Mandible