Alcohol abuse is associated with at least 70% of cases of chronic pancreatitis (CP) and 40% of acute pancreatitis. Yet, only a small percentage of those who abuse alcohol develop pancreatic disease. Clearly there are other biological factors which predispose to the development of pancreatitis and alcohol abuse is acting as a triggering mechanism. But what are these factors? Unfortunately, to date no animal model has been developed that recapitulates alcohol related CP. Therefore, it has been difficult to make progress against this disease. However, we have recently developed two novel mouse models which are sensitive to alcohol and develop severe CP without the need for additional insults. The models involve regulated pancreatic acinar cell specific expression of mutant trypsin molecules. One is an experimental construct that becomes activated upon translation (called Trypon mice). The other involves expression of the R122H trypsinogen mutant (called R122H mice) which is associated with hereditary pancreatitis. Neither of these mutant trypsin molecules induces pancreatitis or any obvious perturbations when expressed as a heterozygote. However, when R122G or Trypon mice are fed an alcohol diet;they develop profound CP. These data support a hypothesis that alcohol sensitizes the pancreas to factors that affect trypsin activation or protection from active trypsin. The goal of this proposal is to understand the mechanisms involved in these effects by pursuing three specific aims.
Aim #1 : Determine whether acute or chronic intake of alcohol is necessary to generate CP in mice expressing mutant trypsin. Alcohol has multiple effects and the effects of acute and chronic alcohol are often opposite. It will be important to understand whether alcohol is required in the short or long term to generate chronic pancreatitis in this model. We will also determine the effects of alcohol on trypsin activity to assess whether trypsin itself is the key mechanism. Together these studies will provide important basic information about the model.
Aim #2 : We will determine the form(s) of acinar cell death initiated in these animals by ethanol. We hypothesize that alcohol perturbs normal cellular mechanisms such that intracellular trypsin induces necrosis in acinar cells. We will also examine whether autophagy is involved in the effects of ethanol in this model.
Aim #3. Determine the role of metallothionein (MT) in the development of CP in alcohol treated mice expressing mutant trypsin. We have previously found that alcohol feeding causes a down-regulation of MT, which normally plays a protective role in acute pancreatitis. To understand the role of MT in alcohol related CP we will examine the effects of mutant trypsin expression in mice with high (Zn treated) or low (MT deficient) levels of MT. We will also investigate the mechanisms of alcohol reduction of MT expression. Together these novel models and approaches will provide important new information about the relationship between alcohol and pancreatic disease.
The development of new treatments for alcohol related pancreatic disease had been hindered by the lack of physiologically relevant animal models. We have developed for the first time an animal model with a modified genetic background that develops alcohol dependent chronic pancreatitis without the need for additional injurious treatments. This new model will provide an opportunity to discover important new details about the role of alcohol in pancreatic disease.
|Swidnicka-Siergiejko, A K; Gomez-Chou, S B; Cruz-Monserrate, Z et al. (2017) Chronic inflammation initiates multiple forms of K-Ras-independent mouse pancreatic cancer in the absence of TP53. Oncogene 36:3149-3158|
|Logsdon, Craig D; Arumugam, Thiruvengadam; Ramachandran, Vijaya (2015) Animal Models of Gastrointestinal and Liver Diseases. The difficulty of animal modeling of pancreatic cancer for preclinical evaluation of therapeutics. Am J Physiol Gastrointest Liver Physiol 309:G283-91|
|Charo, Chantale; Holla, Vijaykumar; Arumugam, Thiruvengadam et al. (2013) Prostaglandin E2 regulates pancreatic stellate cell activity via the EP4 receptor. Pancreas 42:467-74|
|Huang, Haojie; Liu, Yan; Daniluk, Jaroslaw et al. (2013) Activation of nuclear factor-?B in acinar cells increases the severity of pancreatitis in mice. Gastroenterology 144:202-10|
|Ma, Ying; Hwang, Rosa F; Logsdon, Craig D et al. (2013) Dynamic mast cell-stromal cell interactions promote growth of pancreatic cancer. Cancer Res 73:3927-37|
|Logsdon, Craig D; Ji, Baoan (2013) The role of protein synthesis and digestive enzymes in acinar cell injury. Nat Rev Gastroenterol Hepatol 10:362-70|
|di Magliano, Marina Pasca; Logsdon, Craig D (2013) Roles for KRAS in pancreatic tumor development and progression. Gastroenterology 144:1220-9|
|Philip, Bincy; Roland, Christina L; Daniluk, Jaroslaw et al. (2013) A high-fat diet activates oncogenic Kras and COX2 to induce development of pancreatic ductal adenocarcinoma in mice. Gastroenterology 145:1449-58|
|Criscimanna, Angela; Speicher, Julie A; Houshmand, Golbahar et al. (2011) Duct cells contribute to regeneration of endocrine and acinar cells following pancreatic damage in adult mice. Gastroenterology 141:1451-62, 1462.e1-6|
|Ji, Baoan; Logsdon, Craig D (2011) Digesting new information about the role of trypsin in pancreatitis. Gastroenterology 141:1972-5|
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