褪黑素通过miR-128-3p/MAPK14调节内质网自噬改善精母细胞热损伤的分子机制

精子发生需要阴囊的温度低于体温，热应激会导致生精障碍。精索静脉曲张在男性中的发病率为15%，是男性不育的常见因素，其由于静脉淤血使睾丸发生热应激，导致生育力降低甚至不育。课题组前期研究发现热应激导致睾丸损伤，尤其是引起精母细胞内质网应激，导致精母细胞凋亡，而褪黑素通过增加精母细胞miR-128-3p的表达抑制靶基因MAPK14表达，激活内质网自噬，改善精母细胞热损伤，但分子机制不明。据此本项目提出假说：褪黑素通过miR-128-3p调节内质网自噬改善精母细胞热损伤。本项目拟开展以下研究：利用动物实验探究褪黑素通过内质网自噬减缓精母细胞热损伤的作用及分子机制；并在人中进一步验证褪黑素调节内质网自噬改善精索静脉曲张导致不育的作用效果及机制。本研究将从内质网自噬这个新视点揭示褪黑素改善精母细胞热应激损伤的机制，为临床应用褪黑素改善精索静脉曲张导致不育患者的辅助生殖技术治疗结局提供新的思路。

Spermatogenesis requires the scrotum to have a temperature lower than that of the body. Heat stress caused by higher testicular temperature can induce spermatogenic disorders. Varicocele, a common cause of male infertility, affects 15% of men. It causes venous congestion and thus heat stress in the testes, resulting in reduced fertility and even infertility. Our previous research has shown that heat stress causes testicular damage, especially spermatocyte endoplasmic reticulum stress and spermatocyte apoptosis. Our preliminary experiments also found that melatonin activates endoplasmic reticulum autophagy and alleviates spermatocyte damage by upregulating the expression of miR-128-3p and downregulating the expression of the target gene MAPK14, however, the molecular mechanism is unclear. .Based on the existing evidence, the hypothesis of the proposed project is that melatonin alleviates the damage induced by heat stress in spermatocytes through regulation of ER-phagy via miR-128-3p/MAPK14. To test the hypothesis, we will explore the molecular mechanism of melatonin-mediated endoplasmic reticulum autophagy in heat-stressed spermatocytes using animal subjects. Following this, we will verify the role and molecular mechanism of melatonin in improving varicocele related infertility in human subjects. .The goal of our research proposal is to uncover the mechanism underlying melatonin attenuating heat stress damage of spermatocyte through the regulation of ER-phagy, and to advances the knowledge in assisted reproductive technology for treatment of the infertile patients with varicocele.