ERAD和Autophagy通路协同调控proAVP在内质网中质量控制的分子机理与中枢性尿崩症

肽类激素由内质网合成，其分泌水平及功能失调与多种内分泌代谢病密切相关；但目前关于肽类激素在内质网中的质量控制机制还不清楚。申请人长期从事内分泌代谢病及内质网蛋白质量控制的研究，尤其是专注于内质网相关蛋白降解途径（ERAD）的生理学功能；相关研究成果发表在J Clin Invest等杂志。我们前期研究发现ERAD缺失会引起小鼠AVP神经元中错误折叠proAVP无法降解而滞留在内质网，进而引起其分泌缺陷及中枢性尿崩症；但错误折叠proAVP清除的分子机制还不清楚。自噬是内质网中清除错误折叠蛋白的另外一条重要途径，尤其是不溶性错误折叠蛋白的清除。为此，我们构建了AVP神经元特异自噬缺失小鼠，发现其在ERAD缺失条件下是参与proAVP降解的重要途径。本课题希望进一步研究上述两条通路间互相对话维持proAVP成熟的分子机制，为治疗AVP等肽类激素失衡引起的内分泌代谢病的治疗提供新的分子靶标。

Peptide hormones are synthesized by the endoplasmic reticulum (ER), and ER function is essential for safeguarding peptide hormone secretion levels and their physiological function, but the mechanisms underlying the quality control of peptide hormones in ER are currently unclear. The applicant has been studying metabolic diseases and ER protein quantity control for a relatively long time, with a particular focus on the physiological function of ER-associated protein degradation pathway (ERAD), the results of which were published in journals including J Clin Invest, et al. In our previous study, we discovered that ERAD deletion caused the accumulation of misfolded proAVP in the endoplasmic reticulum of mouse AVP neurons that could not be degraded, leading to defective secretion and central diabetes insipidus. Autophagy is another important pathway for degrading misfolded proteins in the ER, especially aggregated misfolded proteins. To this end, we constructed AVP neuron-specific autophagy-deficient mice, which under ERAD-deficient conditions are critical in maintaining AVP production. We plan to further investigate the molecular selective mechanisms of the above two pathways and the degradation of the different folding status of proAVP, and provide new potential therapeutic targets for the treatment of endocrine metabolic diseases caused by imbalance of peptide hormones.