Genetic influences in experimental pancreatitis

描述（由申请人提供）： 胰腺炎是胰腺的一种急性或慢性炎症性疾病，在美国和美国退伍军人群体中导致显着的发病率和死亡率。过去几十年的趋势表明，美国人口中胰腺炎的发病率有所增加。大多数急性胰腺炎病例与酒精或胆结石有关。慢性胰腺炎会导致进行性纤维化和实质丧失，通常继发于反复发作的急性炎症，而酗酒是主要的诱发因素。人们付出了大量的努力来了解胰腺损伤的原因和机制；然而，关于遗传学在改变急性和慢性胰腺炎的易感性和进展方面的作用的知识非常有限。酒精性胰腺炎在男性和非裔美国人中的患病率较高，表明酒精性胰腺炎具有遗传倾向。实验模型的有限性阻碍了对酒精性胰腺炎发病机制的清晰了解。然而，有几种小鼠胰腺炎模型可供使用，其中研究最多的是雨蛙素给药，它可以引起急性和慢性胰腺炎，并且如果与乙醇一起给药则具有协同作用。我们的假设是，可以鉴定出促进或改善胰腺炎程度的遗传修饰因子，并且此类修饰因子可以作为潜在的治疗靶点。这一假设得到了重要的初步结果和出版记录的支持，将通过以下方式进行检验： (i) 鉴定对急性和慢性实验性胰腺炎敏感或具有抵抗力的小鼠品系（目标 1 和 2）； (ii) 利用目标 1 和 2 的小鼠品系，结合蛋白质组学和基因组方法，确定与实验性胰腺炎易感性或耐药性相关的分子途径（目标 3）； (iii) 测试通过肝素靶向凝血途径作为实验性胰腺炎治疗方式的效果（目标 4）。我们目标的完成应显着提高我们对实验性胰腺炎遗传修饰剂的有限知识，并提供有关凝血途径作为治疗目标的效用的见解。然后可以在人类胰腺炎中测试实验模型的发现，并可能带来潜在的新治疗方法。

DESCRIPTION (provided by applicant): Pancreatitis, an acute or chronic inflammatory disease of the pancreas, results in significant morbidity and mortality in the United States and within our US veteran population. Trends over the past few decades show an increased incidence of pancreatitis in the US population. The majority of acute pancreatitis cases are related to alcohol or gallstones. Chronic pancreatitis, which results in progressive fibrosis and loss of parenchyma, is generally secondary to recurrent episodes of acute inflammation with alcohol abuse being a major precipitating factor. Extensive efforts have been dedicated to understanding the causes and mechanisms of pancreatic injury; however, there is very limited knowledge pertaining to the role of genetics in modifying the susceptibility and progression of acute and chronic pancreatitis. A genetic predisposition to alcohol-induced pancreatitis is suggested by its higher prevalence in males as well as in African Americans. A clear understanding of the pathogenesis of alcoholic pancreatitis has been hindered by the limited availability of experimental models. However, several mouse pancreatitis models are available, with the most studied being cerulein administration which can cause acute and chronic pancreatitis and has a synergistic effect if given with ethanol. Our hypothesis is that genetic modifiers can be identified that promote or ameliorate the extent of pancreatitis, and such modifiers serve as potential therapeutic targets. This hypothesis, which is supported by significant preliminary results and publication record, will be tested by: (i) Identifying mouse strains that are susceptible or resistant to acute and chronic experimental pancreatitis (Aims 1 and 2); (ii) Utilizing the mouse strains from Aims 1 and 2, together with proteomic and genomic approaches, to identify molecular pathways that associate with susceptibility or resistance to experimental pancreatitis (Aim 3); and (iii) Testing the effect of targeting the coagulation pathway, via heparin, as a therapeutic modality in experimental pancreatitis (Aim 4). Completion of our aims should markedly improve our limited knowledge regarding genetic modifiers of experimental pancreatitis and provide insights regarding the utility of the coagulation pathway as a treatment target. Findings in the experimental models can then be tested in human pancreatitis, and may lead to potential novel therapeutic approaches.