端粒在细胞衰老过程中发挥核心作用。端粒的缩短和功能失调与人类的衰老及衰老性疾病的发生密切相关。端粒蛋白TPP1在调控端粒维持和端粒酶招募中具有重要作用。在此前用双分子荧光互补平台进行高通量筛选端粒体互作蛋白的研究中，我们发现端粒体蛋白包括TPP1与多种激酶或磷酸酶结合，暗示着它的磷酸化可能对端粒维持起重要作用。为了深入研究TPP1蛋白磷酸化在调控端粒维持和端粒酶招募中的作用和机制，申请人将利用生物化学、分子生物学手段在细胞水平揭示TPP1蛋白磷酸化在端粒调控中的作用；然后运用双分子荧光互补技术分析TPP1蛋白磷酸化所引起的蛋白互作网络的变化；同时制备TPP1蛋白磷酸化突变体基因编辑小鼠，在体内深入研究其在端粒调控和衰老过程中的作用和机制。本研究将推进对TPP1蛋白磷酸化在端粒调控中的功能的了解，并有助于深入理解TPP1蛋白磷酸化在衰老过程中的调控作用及机制。

Telomere play a central role in cellular senescence. Telomere dysfunction or shortening is directly relevant to human aging and a variety of aging related diseases. Telomeric protein TPP1 play an important role in the telomere maintenance and telomerase recruitment. In our previous study, we applied Bimolecular Fluorescence Complementation technology (BiFC) to do high throughput screening of shelterin (also called telosome) interacting protein and found many kinase or phophatase bind to shelterin protein including TPP1, which indicate phosphorylation of TPP1 is important to telomere maintenance. To study detailed mechanism of TPP1 phosphorylation on telomere regulation and telomerase recruitment, firstly we will use molecular biological and biochemical methods to reveal the role of TPP1 phosphorylation on telomere regulation. Then we will use BiFC system to analyse the protein interacting network of TPP1 with or without phosphorylation. Furthermore，we will generate TPP1 phosphorylation mutant mice to study the the function and mechanism of TPP1 phosphorylation in telomere regulation and aging process in vivo. This research will greatly promote our understanding of role of TPP1 phosphorylation in telomere regulation and aging process.