Project Details
Projekt
Gender-dependent mechanisms of autophagy in the transition of acute to chronic pancreatitis
Subject Area
Gastroenterology
Term
from 2017 to 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 328054153
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.
DFG Programme
Research Grants
