Raptor调控减数分裂和性染色体沉默的作用及机制研究

发布时间：2018-04-04 05:50

  本文选题：mTOR　切入点：Raptor　出处：《南京医科大学》2017年硕士论文

【摘要】：雷帕霉素是重要的免疫抑制剂和肿瘤治疗的临床药物,但已被报道能导致男性不育等一系列副作用。雷帕霉素的作用靶标——mTOR信号通路是细胞内重要的代谢调节中枢,主要通过形成两种复合物mTORC1与mTORC2发挥其功能,在蛋白质合成、糖代谢以及细胞骨架形成等众多细胞功能中都扮演了重要角色。这些功能是确保精子发生正常进行的重要基础。减数分裂是生殖细胞独有的细胞分裂方式,也是精子发生过程中至关重要的一环,这一阶段涉及到同源染色体的联会与重组、性染色体沉默(MSCI)等一系列关键步骤,任何一步出错都可能引起减数分裂阻滞,从而导致生精障碍。但mTOR信号通路在雄性生殖细胞减数分裂中的具体作用及机制尚未被阐明。为了研究mTOR信号通路在雄性精子发生及减数分裂中可能存在的作用及分子机制,我们制备了由Ngn3-CRE介导的在生精细胞内对mTORC1核心组分蛋白Raptor基因条件性敲除小鼠。通过对敲除小鼠的表型分析表明,Raptor的敲除导致减数分裂阻滞在粗线期精母细胞。进一步的研究表明,雄性敲除小鼠减数分裂前期染色体的联会和性染色体的沉默受到了影响。综上所述,我们的研究结果证实了 mTORC1信号通路在雄性减数分裂和性染色体沉默中有不可替代的作用。这一发现不仅为雷帕霉素等mTOR抑制剂导致雄性不育提供了更充分的解释,也有助未来开发特异性针对mTORC1信号通路的男性避孕药。
[Abstract]:Rapamycin is an important clinical drug for immunosuppressant and tumor therapy, but has been reported to cause a series of side effects such as male infertility.The target of rapamycin, mTOR signaling pathway, is an important metabolic regulatory center in cells. It plays a role in protein synthesis by forming two complexes, mTORC1 and mTORC2.Glucose metabolism and cytoskeleton formation play an important role in many cellular functions.These functions are an important basis for ensuring normal spermatogenesis.Meiosis is a unique cell division of germ cells and a crucial link in spermatogenesis. This stage involves a series of key steps such as the conjunctions and recombination of homologous chromosomes, the silencing of sexual chromosomes, and MSCI.Any error in any step can lead to meiosis block, which can lead to spermatogenic disorder.However, the role and mechanism of mTOR signaling pathway in male germ cell meiosis has not been elucidated.In order to study the possible role and molecular mechanism of mTOR signaling pathway in male spermatogenesis and meiosis, we have prepared Ngn3-CRE mediated conditional knockout mice in spermatogenic cells on the mTORC1 core protein Raptor gene.Phenotypic analysis of the knockout mice showed that the knockout of Raptor caused meiosis to be blocked in the coarse line spermatocytes.Further studies showed that the synapsis and silencing of sex chromosomes in male knockout mice were affected.In conclusion, our results confirm that mTORC1 signaling pathway plays an irreplaceable role in male meiosis and sex chromosome silencing.The findings not only provide a fuller explanation for male sterility caused by mTOR inhibitors such as rapamycin, but also contribute to the development of future male contraceptives that specifically target the mTORC1 signaling pathway.
【学位授予单位】：南京医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R698.2
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本文编号：1708637