Genetic influences in experimental pancreatitis

实验性胰腺炎的遗传影响

• 批准号: 8762421
• 负责人: Bishr Omary
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8762421
• 关键词: Acute; Acute Disease; African American; Alcohol abuse; Alcoholic Pancreatitis; Alcohols; Animal Model; Biological Models; Caerulein; Cells; Cholelithiasis; Chronic; Chronic Disease; Clinical; Coagulation Process; Data; Deposition; Development; Disease; Drops; Ethanol; Etiology; Experimental Models; Fibrinogen; Fibrosis; Genetic; Genetic Predisposition to Disease; Genomic approach; Genomics; Goals; Health; Heparin; High Prevalence; Human; Incidence; Inflammation; Inflammatory; Injury; Intraperitoneal Injections; Knowledge; Lead; Modality; Modeling; Molecular; Morbidity - disease rate; Mouse Strains; Mus; Pancreas; Pancreatic Injury; Pancreatitis; Pathogenesis; Pathway interactions; Phenotype; Population; Precipitating Factors; Predisposition; Proteomics; Publications; Recurrence; Resistance; Role; Secondary to; System; Testing; Therapeutic; Therapeutic Agents; Toxicant exposure; United States; Veterans; acute pancreatitis; base; chronic pancreatitis; clinical material; comparative genomics; feeding; gamma Fibrinogen; improved; insight; male; meetings; mortality; novel therapeutic intervention; prophylactic; response; success; therapeutic target; trend; Acute; Acute Disease; African American; Alcohol abuse; Alcoholic Pancreatitis; Alcohols; Animal Model; Biological Models; Caerulein; Cells; Cholelithiasis; Chronic; Chronic Disease; Clinical; Coagulation Process; Data; Deposition; Development; Disease; Drops; Ethanol; Etiology; Experimental Models; Fibrinogen; Fibrosis; Genetic; Genetic Predisposition to Disease; Genomic approach; Genomics; Goals; Health; Heparin; High Prevalence; Human; Incidence; Inflammation; Inflammatory; Injury; Intraperitoneal Injections; Knowledge; Lead; Modality; Modeling; Molecular; Morbidity - disease rate; Mouse Strains; Mus; Pancreas; Pancreatic Injury; Pancreatitis; Pathogenesis; Pathway interactions; Phenotype; Population; Precipitating Factors; Predisposition; Proteomics; Publications; Recurrence; Resistance; Role; Secondary to; System; Testing; Therapeutic; Therapeutic Agents; Toxicant exposure; United States; Veterans; acute pancreatitis; base; chronic pancreatitis; clinical material; comparative genomics; feeding; gamma Fibrinogen; improved; insight; male; meetings; mortality; novel therapeutic intervention; prophylactic; response; success; therapeutic target; trend

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.

描述（由申请人提供）： 胰腺炎是胰腺的急性或慢性炎症性疾病，导致美国和美国退伍军人人口的显着发病率和死亡率。在过去的几十年中，趋势表明，美国人口中胰腺炎的发生率增加。大多数急性胰腺炎病例与酒精或胆结石有关。慢性胰腺炎导致进行性纤维化和实质的丧失，通常是继发于急性炎症的复发发作，酒精滥用是主要的沉淀因子。广泛的努力致力于理解胰腺损伤的原因和机制。但是，与遗传学在改变急性和慢性胰腺炎的易感性和进展中的作用有关的知识非常有限。遗传性易感性诱发胰腺炎的原因是男性和非裔美国人的较高患病率。实验模型的可用性有限，对酒精性胰腺炎的发病机理的清晰理解受到了阻碍。然而，有几种小鼠胰腺炎模型可用，其中最多的是给药，可能会导致急性和慢性胰腺炎，如果用乙醇给出协同作用。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剂，并且这种修饰剂是潜在的治疗靶标。该假设得到了重大初步结果和出版记录的支持，将通过以下方式测试：（i）鉴定易感或抗急性和慢性实验性胰腺炎的小鼠菌株（AIMS 1和2）； （ii）利用目标1和2的小鼠菌株以及蛋白质组学和基因组方法，以鉴定与实验性胰腺炎的易感性或耐药性相关的分子途径（AIM 3）； （iii）测试通过肝素作为实验性胰腺炎的治疗方式来靶向凝结途径的效果（AIM 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了解，并就凝结途径作为治疗靶标的实用性提供见解。然后可以在人类胰腺炎中测试实验模型中的发现，并可能导致潜在的新型治疗方法。