PTN-PTPRZ1信号通路促进海马成体神经发生的分子机理研究

神经干细胞增殖和分化产生新生神经元的能力随个体衰老急剧下降，寻找衰老导致成体神经发生缺陷的新靶点对神经功能维持至关重要。PTN是一种重要的神经营养因子，我们已证明神经干细胞分泌的PTN促进新生神经元成熟，但其对神经干细胞自身作用及分子机理尚不清晰。我们发现PTN特异表达在成体海马神经干细胞中，其表达量随着衰老下降，敲降PTN可显著抑制神经干细胞增殖和分化。另外，我们也发现PTN可通过PTPRZ1受体激活AKT信号通路。因此，我们提出假设：调节PTN-PTPRZ1-AKT信号通路可改善衰老导致的成体神经发生缺陷。本项目拟应用PTN条件性敲除小鼠模型探讨PTN在海马成体神经发生的作用，明确PTN是否通过PTPTZ1受体激活AKT信号通路来调控海马神经发生和改善衰老导致的海马神经发生缺陷。结果预期将为延缓衰老提供新的靶点。

The ability of neural stem cells proliferation and differentiation into newborn neurons decreases sharply with individual aging. Finding new targets for adult neurogenesis defects caused by aging is essential for maintaining neurological function. PTN is an important neurotrophic factor. We have proved that PTN secreted by neural stem cells can promote the maturation of newborn neurons. However, its effects on neural stem cells themselves and its molecular mechanism are still unclear. We found that PTN is specifically expressed in neural stem cells of adult hippocampus, and its expression level decreases with aging. Knock-down of PTN can significantly inhibit the proliferation and differentiation of neural stem cells. In addition, PTN can activate AKT signaling pathway through PTPRZ1 receptor. Therefore, we propose that regulating the PTN-PTPRZ1-AKT signaling pathway can ameliorate the neurogenic defects induced by aging. This project intends to use PTN conditional knockout mouse model to explore the role of PTN in the adult hippocampal neurogenesis and to determine whether PTN activates AKT signaling pathway through PTPTZ1 receptor to regulate hippocampal neurogenesis and improve hippocampal neurogenesis defects caused by aging. The results are expected to provide new targets for delaying aging.