胰腺生物钟Stabilizing Loop 调控慢性胰腺炎纤维化进程的作用及分子机制

目前慢性胰腺炎（CP）纤维化发生发展的机制尚未完全阐明；而胰腺作为重要的外周节律器官，其生物钟与内外分泌部疾病的关联倍受关注。我们前期研究发现CP病人和动物模型纤维化胰腺组织、胰腺星状细胞（PSC）活化过程中均存在生物钟Stabilizing Loop的异常表达及节律紊乱；其核心元件Bmal1基因胰腺特异性敲除的小鼠具有自发性胰腺纤维化倾向。因PSC活化与转归失衡是纤维化的促进因素，故此推测胰腺生物钟Stabilizing Loop紊乱介导的PSC持续活化在CP纤维化进程中发挥重要作用。我们拟通过临床病例调查、敲基因小鼠疾病模型研究胰腺生物钟紊乱与CP的关联及其临床意义；以体内外实验阐明CP时Stabilizing Loop紊乱的原因及其调控PSC转分化的分子机制；采用褪黑素干预探讨重置胰腺Stabilizing Loop在CP纤维化中的治疗价值。本研究的完成将为CP临床诊疗开辟全新途径。

Currently, it is unclear how pancreatic fibrogenesis is initiated and progressed in human chronic pancreatitis (CP). As an important peripheral oscillator, the roles for the pancreatic clock in the development of endocrine and exocrine disorders have drawn much attention recently. We previously demonstrated that rhythmic expression of the Stabilizing Loop of pancreatic clockwork was disrupted in CP patients and animal models, as well as in activated pancreatic stellate cells (PSCs). Pancreas-specific knockout of Bmal1, the core component of circadian transcription-translation feedback loops (TTFLs), led to significant spontaneous pancreatic fibrosis in mice. Given that the disbalance of PSC activation and transformation is a key factor for CP fibrogenesis, we thus speculate that continuous PSC activation resulting from dysregulation of the pancreatic Stabilizing Loop plays a pivotal role in the pathogenesis of CP fibrosis. In this study, we aim to clarify the relevance between pancreatic clock misalignment and CP development by clinical investigations and experimental animal studies; to elucidate the mechanism of aberrant pancreatic Stabilizing Loop expression in CP and the mechanism by which the TTFL regulates PSC transdifferentiation using molecular biological methods, both in vitro and in vivo; and to explore the therapeutic potential of melatonin in anti-CP fibrosis through restoring homeostasis of the Stabilizing Loop and pancreatic oscillation. Our work will help unravel the pathogenesis of chronic pancreatic fibrosis and may provide novel insights into the clinical management of CP.