蛋白硫化物异构酶介导PCOS下丘脑神经元内质网应激的研究

In Polycystic ovary syndrome (PCOS), neuroendocrine disorders and dysfunction of neuropeptide secretion play the important role in etiology of PCOS. Previous studies showed that intracellular endoplasmic reticulum stress (ER stress) influenced neuron function. Our recent data has proved that hyperandrogen which mediated protein disulfide isomerases (PDI) induced the expression of ER stress up-regulated and dysfunction of neuropeptide secretion, which might cause PCOS, and inhibition of PDI-ER stress could rescue dysfunction of neuropeptide secretion. Therefore, we deducted that androgen mediated PDI to induce ER stress and dysfunction of neuropeptide secretion, which was one factor of etiological mechanism in PCOS. In future study, the change of PCOS symptom, ER pathway factors and calcium in PCOS animal model will be observed after inhibition of ER stress in hypothalamus, and the mechanism will be clarified through in vivo and in vitro experiments. Furthermore, we will explore the mechanism of neuroendocrinology factors and regulation disorders of HPO axis in PCOS, which demonstrates the etiology and new treatment. The results of our study can have the great value on understanding of the pathogenesis, diagnosis, and therapy of PCOS.

多囊卵巢综合征（PCOS）下丘脑神经元神经肽分泌紊乱是PCOS发生发展的病理生理机制之一。既往研究已提示细胞内质网应激对细胞功能有重要影响。我们的前期工作初步证实，高雄激素可通过内质网细胞因子蛋白硫化物异构酶（PDI）的作用介导内质网应激上调，诱发下丘脑神经肽分泌紊乱，推测可能是PCOS排卵障碍的发病机制之一，抑制PDI-内质网应激可以改善神经肽异常分泌。本项目拟在动物模型中进一步研究下丘脑中的PDI-内质网应激通路相关变化以及下游的神经肽分泌和HPO轴功能改变，观察内质网应激被抑制后神经肽分泌改变以及动物表型改善，从神经内分泌角度阐述PCOS中HPO轴功能紊乱的发生机制，旨在寻找改善PCOS内分泌紊乱、排卵障碍的方法以及新的治疗手段，对其诊断、治疗的研发具有极其重要的指导意义。

多囊卵巢综合征（PCOS）发病机制不明，其中神经内分泌机制有重要作用。下丘脑神经元神经肽分泌异常，是PCOS发病的主要病理生理机制之一。在既往的研究中，细胞内质网应激对细胞功能的重要作用已经被证实，同时，我们既往的研究结果提示，内质网细胞因子蛋白硫化物异构酶（PDI）是高雄激素作用于下丘脑神经元的关键因子，高雄激素可以通过诱导PDI诱发细胞内质网应激甚至凋亡，从而导致下丘脑神经肽分泌紊乱，可能是PCOS发病的重要机制。本研究在细胞模型和动物模型上均证实了高雄激素可以通过PDI的作用诱发内质网应激及细胞凋亡，同时可以通过阐述神经肽的作用逆转应激水平。本研究从神经内分泌角度阐述了PCOS发病机制，为寻找PCOS内分泌紊乱、排卵障碍的方法以及治疗手段提供了理论基础与试验依据，对其诊断、治疗的研发具有重要的指导意义。