Accumulation of excess or misfolded proteins is one cause of ER-stress in the cell. To protect the cell from ER-stress related cell death a multitude of different mechanisms are activated to counteract ER-stress. Within this subproject the role of the transcription factor ATF6 and the ubiquitin ligases UBR1 and UBR2 are going to be examined during the time period of experimental pancreatitis in different mouse models.
The activation of transcription factor ATF6 results in the expression of ER-stress reducing proteins like chaperons or proteasome complexes. Chaperons help to correctly refold misfolded proteins. Proteasome complexes induce the degradation of excess proteins. To investigate the role of ATF6 during pancreatitis a pancreas specific knockout mouse model of ATF6 is going to be used. These experiments will clarify the role of ATF6 and ER-stress during the development of pancreatitis and under physiological conditions.
The ubiquitin ligases UBR1 and UBR2 are responsible for marking unnecessary and misfolded proteins and finally introduce them to the proteasome degradation process. It is well known that pancreatic proteases are targets of UBR1 and that a defect within this mechanism results in the accumulation of digestive enzymes within the acinar cells which leads to a more severe phenotype of pancreatitis with a higher level of intracellular protease activation. Deletion mutations in UBR1 are responsible for the Johanson-Blizzard-syndrome, a severe genetic disease. Patients with Johanson-Blizzard-syndrome have a low life expectancy, severe birth deformities and a total loss of pancreatic function. This illustrates the importance of a functioning protein degradation mechanism. The aim of this project is to investigate the role of UBR1 and UBR2 during pancreatitis. The subproject will study the pancreatitis phenotype in UBR1 and UBR2 deleted mice as well as in double knockout mice. This will help to understand the mechanisms of protein degradation and the impact of protein homeostasis for the normal function of the pancreas.
Supervisors
Prof. Dr. med. Markus M. Lerch
Dr. rer. nat. Matthias Sendler
Team