CRIP1与斑马鱼衰老的相关性及作用机制研究

It has been found that CRIP1 in human peripheral blood mononuclear cells increased with age, suggesting that CRIP1 may be associated with aging. We have also found that expression of crip1 markedly increased with age in zebrafish, and compared with wide type zebrafish (crip1+/+), aging biomarkers which generally decrease with age increased significantly in mutant zebrafish (crip1-/-). These data together suggest that CRIP1 knockout may delay aging. However, what is the correlation between CRIP1 and aging needs further detailed study. Moreover, what is its mode of action is still not clear. These questions above thus form the current research proposal. We plan to use zebrafish (crip1-/-) as model, to examine the effect of CRIP1 on lifespan, aging markers (histologic and molecular markers) production and antioxidant capacity, and to analyze the differently expressed genes and signal pathways in crip1 mutant through transcriptome sequencing. These studies will certainly shed lights on the activities and modes of action of CRIP1 on fish aging, eventually contributing to the prolonging of human healthy lifespan.

人外周血单核细胞中富含半胱氨酸的小肠蛋白（CRIP1）表达量随年龄增加呈上升趋势，推测CRIP1与衰老相关。我们前期研究发现斑马鱼crip1的表达量也随月龄增加而上升，同时发现与野生型（crip1+/+）斑马鱼比较，随月龄增加而含量下降的衰老标记物在突变型（crip1-/-）中呈现出明显上升趋势。这些结果初步表明CRIP1突变可能延缓衰老。然而，这还需要更多证据证明。再者，其作用机理如何？这些都需要深入研究，而这也正好构成了本项申请的主要研究内容。我们拟以突变型（crip1-/-）斑马鱼为模型，研究CRIP1与斑马鱼寿命的关联性及其对衰老标记物（组织学标记物和分子学标记物）表达的影响，同时结合转录组测序分析鉴定crip1缺失引起的基因表达及信号通路变化。本研究将阐明CRIP1突变是否具有延缓衰老作用及可能的作用机制，有望取得具有原创性的研究成果，为有机体抗衰老乃至人类延长寿命提供有益参考。

人外周血单核细胞中富含半胱氨酸的小肠蛋白（CRIP1）表达量随年龄增加呈上升趋势，推测CRIP1与衰老相关。那么，CRIP1突变能否延缓衰老，以及具体作用机理如何，都需要深入研究，而这也正好构成了本项申请的主要研究内容。我们在已建立的斑马鱼CRIP1突变体的基础上，研究发现斑马鱼crip1的表达量也随月龄增加而上升，同时发现与野生型（crip1+/+）斑马鱼比较，随月龄增加而含量下降的衰老标记物在突变型（crip1- /-）鱼中呈现出明显上升趋势。老年突变型（crip1-/-）斑马鱼和野生型（crip1+/+）斑马鱼相比，脂褐素积累减少，蛋白氧化和脂质氧化水平降低。突变型（crip1-/-）斑马鱼比野生型（crip1+/+）斑马鱼抗氧化系统中抗氧化酶活性增加，活性氧水平降低和p66shc表达量下降。这些结果初步表明CRIP1突变可能会延缓斑马鱼衰老。由此得出，CRIP1突变可能有延缓衰老功能，有望取得具有原创性的研究成果，为有机体抗衰老乃至人类延长寿命提供有益参考。