神经干细胞衰老是引发神经退行性疾病的一个重要原因。p16Ink4a是细胞衰老的主导基因，主要通过与细胞周期依赖激酶4（Cdk4）的相互结合而引发细胞衰老。我们的前期研究结果表明，基于p16Ink4a与Cdk4的结合位点设计的p16Ink4a多肽抑制剂降低羟基脲所致的神经干细胞生长阻抑;还可改善SAMP8快速老化小鼠的学习记忆功能。因此，本课题将基于p16Ink4a与Cdk4的结合位点，设计并筛选有效的p16Ink4a多肽抑制剂，在羟基脲诱导的神经干细胞衰老模型中，观察其对神经干细胞增殖能力、衰老形态和DNA损伤应激反应的影响; 进而利用SAMP8快速老化小鼠研究p16Ink4a多肽抑制剂对小鼠衰老表型、寿命和学习记忆能力的影响；最后研究p16Ink4a多肽抑制剂对自噬和抗氧化途径的影响，以明确p16Ink4a多肽抑制剂延缓神经干细胞衰老的作用及其机制，从而为抗衰老药物研发提供实验依据。

The senescence of neural stem cell is an important cause of neurodegenerative disease. p16Ink4a is a dominant gene for cellular senescence. The deletion of its functions can delay senescence. Studies have shown that p16Ink4a trigger cell senescence mainly through the interaction with cell cycle-dependent kinase 4 (Cdk4). Recently, we found that the peptide inhibitor of p16Ink4a based on the interaction domain between p16Ink4a and Cdk4 could rescue the hydroxyurea-induced growth inhibition in neural stem cells. Furthermore, the peptide inhibitor of p16Ink4a could improve the activities of learning and memory in SAMP8 mice. Therefore, we will use rational design to identify short peptide inhibitors of the protein-protein interaction between p16Ink4a and Cdk4. To clarify anti-aging effects of selective peptide inhibitor of p16Ink4a and its associated molecular mechanisms, we will: ① test the effects of selective peptide inhibitor of p16Ink4a on cell proliferation, senescence morphology and DNA damage stress response in hydroxyurea-treated neural stem cells; ② examine its effects on aging phenotypes, life span, tumor incidence, learning and memory in SAMP8 mice; ③ examine the effects of selective peptide inhibitor of p16Ink4a on autophagy and antioxidant pathways. It will help to provide experimental evidence for anti-aging drug development.