小鼠睾丸中VLC-PUFAs的生物合成、调控及功能研究

哺乳动物视网膜、睾丸及精子中存在26C～40C的极长链多不饱和脂肪酸（VLC-PUFAs），主要由极长链脂肪酸延长酶4（Elovl4）催化合成。已有研究基本阐明VLC-PUFAs在视网膜中的生理功能，证实Elovl4突变导致视网膜不能合成VLC-PUFAs，进而产生人类Stargardt黄斑营养不良视网膜病变(STGD3)。然而，睾丸及精子中VLC-PUFAs的生理功能及其合成调控等尚未阐明。本项目利用慢病毒介导的RNA干扰Elovl4小鼠模型、睾丸特异性敲除Elovl4小鼠模型、Fat1/D4转基因小鼠模型及添加不同脂肪酸饲喂小鼠获得降低或改变睾丸及精子中VLC-PUFAs含量及类型而研究其功能，确定VLC-PUFAs是否是维持睾丸功能和精子发生、成熟所必须的物质，证实ω-6与ω-3VLC-PUFAs对维持雄性生殖功能的异同，并分析睾丸中合成VLC-PUFAs的前体物是否为从头合成。

Mammalian retina, testis and sperm contain very long-chain polyunsaturated fatty acids (VLC-PUFAs) with 26~40 carbons, which are mainly catalyzed by very long-chain fatty acid elongase 4 (Elovl4). Studies have largely elucidated the physiological function of VLC-PUFAs in the retina, confirming that Elovl4 mutations lead to the inability of the retina to synthesize VLC-PUFAs, which in turn results in human Stargardt-like macular dystrophy type3 (STGD3). However, the physiological function of VLC-PUFAs and its synthesis and regulation in testis and sperm have not been fully elucidated. This project uses several type of mouse models, including lentivirus-mediated RNA interference targeting Elovl4 mouse model, testis specific Elovl4 knockout mouse model, Fat1/D4 transgenic mouse model and mice fed with different type of fatty acids, to reduce or change the VLC-PUFAs content and type in testis and sperm for the research of VLC-PUFAs function. We also seek to determine whether VLC-PUFAs is necessary for testicular function, sperm occurrence and maturation, confirm the similarities and differences between ω-6 and ω-3 VLC-PUFAs in maintaining male reproductive function, and analyze whether the precursors for VLC-PUFAs synthesis in the testis are de novo synthesized.