Gender-dependent mechanisms of autophagy in the transition of acute to chronic pancreatitis

自噬描述细胞器和蛋白质聚集体在细胞内的降解。因此，自噬降解的目标不仅是功能失调的细胞器，而且还为细胞生长提供代谢底物。多个蛋白质复合体和接头蛋白参与了自噬。胰腺高度依赖于营养和能量的供应，因为它产生大量具有侵略性的消化酶。此外，胰腺腺泡细胞需要机制来防止胰腺内消化酶的激活，从而防止胰腺炎。自噬和胰腺炎在过去的研究中是相关的，尽管潜在的功能联系还没有被揭示。我们研究小组的研究结果表明，胰腺特异性ATG5的缺失会导致胰腺外分泌组织的进行性破坏，并引发慢性胰腺炎症。ATG5基因缺陷的小鼠不仅会患上慢性胰腺炎，还会患上糖尿病。有趣的是，胰腺退化的程度不仅取决于小鼠的性别，还取决于自噬失活的时间点。在成人胰腺中，ATG5基因失活对胰腺形态无影响。雄性小鼠更容易患上慢性胰腺炎和糖尿病。另一方面，雌性小鼠对自噬功能的丧失具有抵抗力。依赖ATG5的自噬丧失会导致性激素调节基因转录的变化，再次强调自噬与胰腺性别之间的联系。此外，p62的缺失对急性胰腺外分泌损伤的程度也有性别依赖性的影响。借助各种小鼠和胰腺炎症模型，我们计划解剖和分析急性胰腺炎向慢性胰腺炎性别依赖性转变中涉及的信号通路。在一个三方工作计划中，我们将应用体内各种方法(去势、激素补充、急性胰腺炎诱导)、机械/全局分析(代谢组学/转录组学)以及多种小鼠模型，回答以下问题：自噬和性激素在慢性腺泡细胞损伤的调节中是如何联系的？依赖p62的自噬如何影响雄性和雌性小鼠的急性腺泡细胞损伤？哪些信号通路在急性胰腺损伤向慢性胰腺损伤的转变中起作用？我们的目标是阐明自噬在急性胰腺炎向慢性胰腺炎转变过程中的作用，并强调在这些模型中可检测到的性别依赖效应。

Autophagy describes the intracellular degradation of organelles and protein aggregates. Thereby, autophagic degradation targets not only dysfunctional organelles but also provides metabolic substrates for cellular growth. Multiple protein complexes and adaptor proteins are involved in autophagy. The pancreas is highly dependent on the provision of nutrients and energy as it produces an ample amount of aggressive digestive enzymes. In addition, the pancreatic acinar cell requires mechanisms for protection against intra-pancreatic digestive enzyme activation and therefore pancreatitis.Autophagy and pancreatitis have been associated in past studies, although the underlying functional connection has not been unveiled yet. Results from our research group have shown that pancreas specific loss of Atg5 leads to progressive destruction of the exocrine pancreatic tissue and initiates chronic pancreatic inflammation. Atg5-deficient mice not only develop chronic pancreatitis but also diabetes.Interestingly, the degree of pancreatic degeneration depends not only on the gender of the mice but also on the time point of autophagy inactivation. In the adult pancreas, genetic inactivation of Atg5 has no influence on pancreatic morphology. Male mice are more susceptible to the development of chronic pancreatitis and diabetes. Female mice on the other hand are resistant against loss of autophagic function.Loss of Atg5-dependent autophagy leads to changes in the transcription of sex hormone regulated genes highlighting once more the connection between autophagy and gender in the pancreas. Moreover, deletion of p62, an important autophagy adaptor, also has a gender-dependent influence on the degree of acute exocrine pancreatic damage.With the help of various mouse and inflammatory models of the pancreas, we plan to dissect and analyze signaling pathways involved in the gender-dependent transition of acute to chronic pancreatitis.In a three-partite working program we will apply various in vivo methods (castration, hormonal supplementation, induction of acute pancreatitis), mechanistic/ global analyses (metabolomics/ transcriptomics) as well as multiple mouse models, to answer the following questions:How are autophagy and sex hormones connected in the regulation of chronic acinar cell damage? How does p62-dependent autophagy influence acute acinar cell damage in male and female mice? What signaling pathways play a role in the transition of acute to chronic pancreatic damage?Our goal is to clarify the function of autophagy in the transition of acute to chronic pancreatitis and highlight the gender-dependent effects detectable in these models.