HDACs in pancreatic recovery after injury

描述(申请人提供)：胰腺炎是一种严重的、危及生命的疾病，目前还没有针对性的治疗方法。大多数关于这种疾病的研究都考察了损伤后的炎症途径。另一种新的替代策略是检查胰腺对损伤的恢复机制。基于三个关键观察：(1)丙戊酸(VPA)是一种与胰腺炎相关的药物，是一类重要的表观遗传蛋白组蛋白脱乙酰酶(HDACs)的抑制剂；(2)HDACs介导胰腺发育；(3)胰腺发育的要素在胰腺恢复过程中被重述--我们假设HDACs对于激活胰腺恢复所需的程序至关重要。使用两个复杂的恢复实验模型，AIM 1将确定HDAC是否调节损伤后的胰腺恢复，AIM 2将确定受HDAC影响的恢复过程中的关键发育途径，AIM 3将使用可诱导的腺泡特异性条件HDAC基因敲除来确定特定胰腺细胞类型的HDAC是否调节胰腺恢复。在初步数据中，我们证明了在恢复的高峰期，共同的HDAC亚型的表达和HDAC活性都增加了，VPA对HDAC的抑制延迟了恢复，并调节了关键的胚胎转录因子和驱动腺泡细胞再分化的信号通路。预计这些研究不仅将提供对 药物相关性胰腺炎的发病机制尚不清楚，但更重要的是，这项工作将开辟一种新的治疗模式，利用表观遗传学来控制胰腺的恢复和再生。

DESCRIPTION (provided by applicant): 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.