神经发生在下丘脑垂体柄损伤致中枢性尿崩的作用机制研究

Hypothalamic-pituitary injury often results in serious hypothalamic dysfunction and endocrine disorder, it’s commonly occur in hypothalamic tumor, craniocerebral injury and cerebral hemorrhage. The incidence and the long-term mortality of central diabetes insipidus (CDI) stay in high level, and its prognosis is poor. In the animal model of CDI induced by pituitary stalk injury, we found that the long-term urine volume tended to be normal and the hormone disorder could be compensated. If the mechanism of recovery compensation can be figure out and applied to clinic, the hypothalamic dysfunction would be better managed. In previous studies, we found that hypothalamic neurogenesis occurred after hypothalamic pituitary stalk injury, Nkx2.1 neural precursor cells (NPCs) were activated in median eminence, and new cells migrated to upstream nuclei and differentiate into neurons subsequently . RNA sequencing and PCR indicated that Lhx2 was involved in the neurogenesis of median eminence after hypothalamic pituitary stalk injury. Next, we will verify the differentiation fate and regulation of Nkx2.1 NPCs by Lhx2 in vitro and in vivo experiments. Furthermore, we will confirm that the new neurons may integrate into the original neural circle which possess endocrine regulation. Finally, we will confirm the relationship between neurogenesis and the prognosis of CDI by up or down-regulation of neurogenesis level, thereby we can systematically elucidate the mechanism of neurogenesis involved in the recovery from hypothalamic injury. This project will provide a new strategy for the treatment of hypothalamic injury, improve the prognosis of patients with hypothalamic dysfunction, which have important social benefits.

下丘脑肿瘤、颅脑损伤、脑出血等易导致下丘脑垂体损伤，继而并发严重的内分泌障碍。以中枢性尿崩发病高，长期死亡率高，预后不佳。在垂体柄损伤的中枢性尿崩动物模型中发现，远期尿量趋于正常，激素紊乱得以代偿。倘若能发现其中的恢复代偿机制并加以应用，则可更好的管理下丘脑功能紊乱。前期我们发现下丘脑垂体柄损伤后出现下丘脑神经发生，正中隆起Nkx2.1前体细胞激活，且有新生细胞迁移至上游核团分化为神经元，进而测序和PCR筛选发现Lhx2参与损伤后正中隆起神经发生，下一步拟通过对Nkx2.1前体细胞进行体内外的干预，阐明Lhx2前体细胞的分化命运及参与的调控机制，并证实该新生的神经元整合至神经环路具有内分泌调控作用。最后拟通过调节神经发生水平验证与中枢性尿崩的预后关系，从而系统地阐述神经发生参与下丘脑损伤修复的机制作用。本项目将为下丘脑功能紊乱的治疗提供新策略，具有重要的社会效益。

内环境体液稳态对生存至关重要。下丘脑神经垂体系统（HNS）的完整性是精确调节体液代谢和精氨酸加压素（AVP）激素释放的重要基础。临床上，部分由HNS病变引起的中枢性尿崩症（CDI）患者可经历体液代谢的恢复代偿。然而，下丘脑是否具有结构可塑性和病理条件下自我修复的潜力仍不清楚。本研究通过构建垂体柄电损伤（PEL）模型，研究下丘脑损伤后正中隆起（ME）中新的神经垂体样结构的修复和重建。我们表明，活化和增殖的成年神经祖细胞分化成新的成熟神经元，然后与重塑的AVP纤维整合，重建PEL后ME中的局部AVP激素释放神经回路。我们发现NK2同源盒1（NKX2.1）的转录因子和NKX2.1介导的声波刺猬信号通路是成人下丘脑神经发生的关键调节因子。综上所述，我们的研究提供了证据，证明成人ME神经发生参与AVP释放回路的结构重建，并最终在下丘脑自我修复期间恢复体液代谢稳态。