Pancreatitis is a severe, life-threatening disorder for which there are currently no targeted therapies. Most studies of this disease examine the inflammatory pathways following injury. A novel, alternate strategy would be to examine the recovery mechanisms of the pancreas in response to injury. Based on three key observations: (1) that valproic acid (VPA), a drug which is definitely associated with pancreatitis, is an inhibior of an important class of epigenetic proteins the histone deacetylases (HDACs); (2) that HDACs mediate pancreas development; and (3) that elements of pancreas development are recapitulated during pancreatic recovery-we hypothesized that HDACs are crucial for activating the programs necessary for pancreatic recovery. Using two sophisticated experimental models of recovery, Aim 1 will determine whether HDACs modulate pancreatic recovery after injury, Aim 2 will determine the key developmental pathways during recovery that are affected by the HDACs, and Aim 3 will use inducible acinar-specific conditional Hdac knockouts to determine whether HDACs within specific pancreatic cell types modulates pancreatic recovery. In preliminary data, we demonstrate that both expression of a common HDAC isoform and HDAC activity are increased at the peak of recovery, that HDAC inhibition with VPA delays recovery and modulates key embryonic transcription factors and signaling pathways that drive acinar cell redifferentiation. It is anticipated that these studies will not only provide an understanding of a mechanism of drug-induced pancreatitis, namely due to VPA, but more importantly, the work will open up a new therapeutic paradigm that exploits epigenetics to control recovery and regeneration of the pancreas.
Acute pancreatitis is a painful and life-threatening disease of the pancreas for which we have no specific treatments. Based on (1) the clinical observation that valproic acid (VPA), a drug that has a definite association with pancreatitis, blocks an important class of epigenetic proteins called the histone deacetylases (HDACs), (2) the finding that HDACs mediate pancreas development, and (3) that pancreas development is recapitulated during pancreatic recovery, we will use sophisticated models of pancreatic injury and subsequent recovery to systematically examine the role of HDACs in this context. We are hopeful that our studies will open up a new paradigm to understand epigenetic mechanisms that control recovery and ultimately mediate regeneration in the pancreas.
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