SSTR1在调控继发性甲状旁腺功能亢进中的作用及机制研究

Because patients with secondary hyperparathyroidism (SHPT) could not fully benefit from medicine therapy or surgery with huge health damage due to SHPT, it is urgent to investigate the mechanism of SHPT. We analyzed the RNA sequencing results of miscut normal parathyroid from patients with benign thyroid entities and proliferative parathyroid from patients with SHPT. Somatostatin receptor 1 (SSTR1) was confirmed to be overexpressed in SHPT. SSTR ligand analogue is used to treat neuroendocrine neoplasms with the overexpression of SSTR. These results indicate that SSTR1 is a new candidate target for the treatment of SHPT. Based on our previous study and literature review, we hypothesize that SSTR1 pathway inhibits the secretion of parathyroid hormone (PTH) via cAMP pathway and inhibits the synthesis of PTH and the proliferation of parathyriod cells by ERK pathway. We attempts to determine the role of SSTR1 in the control of SHPT including cell test, animal experiment and clinical samples. Our study will clarify the molecular mechanisms that SSTR1 modulates SHPT, and confirm the new-generation somatostatin analogue pasireotide for effective control and treatment of SHPT, with great theoretical significance and applicable value.

继发性甲状旁腺功能亢进（Secondary hyperparathyroidism, SHPT）危害大，疗效仍不理想，迫切需要对SHPT展开研究。项目组对SHPT增生甲状旁腺和手术误切的正常甲状旁腺进行RNA测序，发现并证实生长抑素受体1（somatostatin receptor 1, SSTR1）在SHPT组织中明显增高。SSTR配体类似物已被用于治疗高表达SSTR的神经内分泌肿瘤。这提示SSTR1可能成为临床治疗SHPT的全新靶点。项目组基于文献和前期工作，提出科学假说：SSTR1信号通路通过cAMP通路抑制甲状旁腺激素（PTH）分泌；通过ERK通路抑制PTH合成和甲状旁腺细胞增殖。 项目组拟从细胞、动物实验、临床标本三层面探讨SSTR1在调控SHPT中的作用。本项目将阐明SSTR1调控SHPT的分子机制，证明新一代生长抑素类似物帕瑞肽可有效防治SHPT，具有重要的理论和临床意义。

继发性甲状旁腺功能亢进(Secondary hyperparathyroism, SHPT)是慢性肾脏病(chronic kidney disease, CKD)终末期由于钙磷代谢紊乱引起的常见、严重且费用昂贵的并发症。SHPT与尿毒症患者骨质疏松、骨折、神经系统损害以及心血管不良事件的发生显著相关，严重危害尿毒症患者的生存质量和预后.本研究通过探讨SSTR家族、HER家族和DPP4是否在继发性甲状旁腺功能亢进的发生发展中起关键作用，进一步探究继发性甲状旁腺功能亢进的发病机制；并通过宏基因组、靶向代谢组以及动物实验初步探究肠道菌群紊乱与SHPT发病过程的潜在联系。.结果：（1）RNA-seq测序筛选出继发性甲状旁腺功能亢进与正常甲状旁腺差异性基因；（2）Real-time qPCR在mRNA层面验证EGFR、ERBB2、ERBB3、ERBB4、SSTR1、SSTR2和DPP4结果与测序相符；（3）免疫组化在蛋白质层面检测EGFR、ERBB4、SSTR1、SSTR2和DPP4结果与测序相符；（4）通过5/6肾切除SD大鼠并高磷饲料喂养构建了继发性甲状旁腺功能亢进模型；（5）Pasireotide干预继发性甲状旁腺功能亢进模型大鼠可以降低PTH水平;（6）尿毒症有/无SHPT患者粪便及SHPT模型大鼠粪便中发现大量产短链脂肪酸菌群丰度下降，丁酸含量显著下降;（7）丁酸钠灌胃干预继发性甲状旁腺功能亢进模型大鼠可以降低PTH水平，同时恢复肠道菌群稳态。.结论： SSTR1是继发性甲状旁腺功能亢进的干预靶点，SST类似物Pasireotide可以抑制继发性甲状旁腺模型的甲状旁腺素的增加及甲状旁腺细胞的增殖。丁酸钠是防治继发性甲状旁腺功能亢进的有效靶点，丁酸钠灌胃可预防肾功不全大鼠模型出现甲状旁腺素增加及甲状旁腺增生。.本项目阐明了SSTR1调控 SHPT 的分子机制并初步探究肠道效应产物短链脂肪酸在SHPT发病中的作用，证明新一代生长抑素类似物帕瑞肽及丁酸钠可有效防治 SHPT，具有重要的理论和临床意义，为 SHPT患者带来新的福音与希望。