磷转运蛋白对寿命调控的机理研究

Currently, environmental pollution of inorganic Pi is prominent and large amounts of Pi accumulate in soil, water and human food. It has been reported that inhibition of Pi intake can significantly extend the life span of animals. Previous studies in our laboratory demonstrated that specific knock down of dPiT, homologous of human phosphate transporter PiT2, in nervous system can significantly prolong the life span of flies. It may be a novel gene involving in the regulation of lifespan. It is well known that several signaling pathways regulate the animal lifespan, including insulin signaling, MAPK signaling, AMPK signaling and mTOR signaling pathways. In this study, we will use genetic, biochemical and immunochemistry approaches in a Drosophila model to investigate whether dPiT regulates the lifespan of fruit flies independently or through cross-talking with these pathways. This study will demonstrate how inorganic Pi affect the lifespan of animals and facilitate us understanding the regulation of lifespan by environment and genetics and provide a new target for extending life span.

目前环境中的无机Pi污染严重，土壤、水源和人类的食物中存在大量的Pi的累积。已有研究报道抑制Pi的摄取可以明显延长动物体寿命。本实验室前期研究发现神经系统特异敲减钠磷同向协同转运蛋白dPiT能够明显延长果蝇的寿命,是一个可能参与寿命调控的基因。dPiT为人类编码PiT1及PiT2蛋白的SLC20A1及SLC20A2的同源基因。目前已知可与调控动物体寿命的信号通路包括胰岛素信号通路、MAPK信号通路、AMPK信号通路及TOR信号通路。本研究以果蝇为模型拟通过遗传学、生物化学及分子生物学等方法阐明dPiT是否与参与这些信号通路对寿命的调控，亦或是存在与上述信号通路没有关联的另一种参与寿命调控的信号通路，以期为动物体寿命研究提供新的靶点。该项研究最终可以解答无机Pi对动物体寿命的影响，以帮助我们更全面更系统的了解参与寿命调控的环境因素及遗传因素。

我们前期研究结果显示在果蝇神经系统中敲降钠磷转运蛋白dPit，明显延长果蝇的寿命。dPit是哺乳动物的三型钠磷转运蛋白Pit1和Pit2编码基因在果蝇中的同源基因。Pit2突变可以减少细胞对无机磷的吸收。本研究通过转录组测序分析比较野生型与dPit突变体，筛选无机磷转运蛋白dPit的互作蛋白。结果显示显著差异表达的基因没有富集到已知的与寿命相关的胰岛素、MAPK、AMPK及Tor信号通路上。因此，dPit参与寿命调控可能是通过其他通路完成的。据报道，klotho突变影响小鼠的寿命，而体内磷平衡在klotho对寿命的控制中起关键作用。Klotho在野生型果蝇的酱色细胞中表达（与人类肝脏功能类似），通过分泌进入神经系统。在果蝇中Klotho突变可以明显减少果蝇寿命。klotho突变还会导致果蝇脂质代谢异常，饥饿条件下会出现降色细胞内脂滴累积增多。脂质代谢与动物体寿命密切相关，因此，dPit有可能与klotho互作调节脂代谢参与寿命调控。