Pancreatic Regeneration from Alcohol-Associated Injury

酒精相关损伤的胰腺再生

• 批准号: 8959797
• 负责人: Lisa A. Elferink
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-10 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8959797
• 关键词: Acinar Cell; Address; Adoption; Adult; Affect; Alcohol consumption; Alcoholic Pancreatitis; Alcoholic beverage heavy drinker; Alcohols; Apoptosis; Attenuated; Automobile Driving; Biological Assay; Cell Survival; Cells; Chronic; Coupled; Data; Defect; Disease; Duct (organ) structure; Ductal; Ductal Epithelial Cell; Ductal Epithelium; Employee Strikes; Enzymes; Epithelium; Ethanol toxicity; Exocrine pancreas; Fibrosis; Figs - dietary; Future; Gene Expression Profile; Genetic; Health; Human; Inflammation; Inflammation Mediators; Inflammatory Response; Injury; Knock-out; Knockout Mice; Knowledge; Link; Mediating; Mediator of activation protein; Metaplasia; Metaplastic; Modeling; Mus; Natural regeneration; Pancreas; Pancreatic Injury; Pancreatitis; Population; Process; Proto-Oncogene Protein c-met; Research; Risk Factors; Role; Secretory Cell; Signal Transduction; Specimen; Stem cells; Testing; Tissues; Up-Regulation; alcohol effect; alcohol exposure; alcohol response; chemokine receptor; chronic pancreatitis; design; feeding; injured; macrophage; meetings; novel; progenitor; repaired; research study; response; self-renewal; stem; therapeutic target; tissue repair; treatment strategy

 DESCRIPTION (provided by applicant): The association between high alcohol intake and necroinflammatory diseases such as pancreatitis has been well documented for over 100 years. However, only 5% of heavy drinkers develop pancreatitis, implying the existence of adaptive mechanisms that restore pancreatic tissue following alcohol-associated injury. Remarkably, the mechanisms critical for pancreatic repair and regeneration following alcohol-associated injury are neither comprehensively analyzed nor fully understood. Thus this proposed research aims to characterize mechanisms important for the regeneration of pancreatic acinar cells, specialized secretory cells that are the primary target in alcoholic pancreatitis. Our preliminary studies highlight the importance of the Hepatocyte Growth Factor Receptor (MET) as an intrinsic survival and/or repair mechanism for acinar cells. Our studies show that MET signaling is low in normal adult pancreas. However, MET levels are elevated in ductal and acinar cells in human pancreatitis specimens, consistent with a role for MET as an adaptive repair mechanism. We also show that genetic deletion of MET in adult murine acinar cells is linked to increased acinar cell apoptosis, chronic inflammation with fibrosis following alcohol-associated injury. Notably we also found an extensive ductal metaplasia in alcohol-fed mice lacking MET, possibly through the expansion of a stem/ progenitor cell population. Finally, we identified specific alterations of the pancreatic transcriptome mediated by MET signaling during alcohol-associated injury, key for tissue repair and inflammation. Of note, loss of MET signaling results in an up-regulation of CCR2, an important mediator of chronic inflammation. Our preliminary studies support the novel hypothesis that MET signaling promotes acinar regeneration in response to alcohol-associated injury. This hypothesis will be tested in two specific aims. In Aim 1, we will show that MET signaling is indispensable for Acinar-Ductal Metaplasia (ADM), the primary mechanism by which acinar cells restore their numbers following damage. To do this we will use a novel conditional MET knockout mouse specific for adult acinar cells, thereby sparing ductal and progenitor cells, coupled with a ex vivo ADM assay. We will examine the role of MET for specific steps leading to ADM including a) acinar trans differentiation into a ductal-like epithelia and/or b) subsequent redifferentiation of the metaplastic epithelia into functional acina cells. In Aim 2, we will illustrate that loss of MET enhances a CCR2- mediated inflammatory response that exacerbates alcohol-associated injury. Using a targeted pharmacological approach in our MET knockout model of alcohol-associated damage, we will examine the role of CCR2 signaling in acinar injury and whether this signaling may be leveraged to promote acinar renewal. Collectively, the results of our experiments will uncover a novel role for MET in ADM and reducing chronic inflammation, which may result in targeted therapeutics to promote repair of the exocrine pancreas due to alcohol-associated injury.

 描述（由申请人提供）： 100 多年来，大量饮酒与胰腺炎等坏死性炎症疾病之间的关联已得到充分记录，然而，只有 5% 的酗酒者会患上胰腺炎，这意味着存在恢复胰腺组织的适应性机制。值得注意的是，酒精相关损伤后胰腺修复和再生的关键机制既没有得到全面分析，也没有得到充分理解，因此这项研究旨在表征对酒精相关损伤重要的机制。胰腺腺泡细胞的再生是酒精性胰腺炎的主要靶标，我们的初步研究强调了肝细胞生长因子受体（MET）作为腺泡细胞内在存活和/或修复机制的重要性。正常成人胰腺中的 MET 信号传导水平较低，但人类胰腺炎标本中的导管和腺泡细胞中 MET 水平升高，这与 MET 作为适应性修复机制的作用一致。研究表明，成年小鼠腺泡细胞中 MET 的基因缺失与腺泡细胞凋亡增加、酒精相关损伤后的慢性炎症和纤维化有关，值得注意的是，我们还在缺乏 MET 的酒精喂养小鼠中发现了广泛的导管化生，这可能是通过扩张造成的。最后，我们确定了酒精相关损伤期间由 MET 信号传导介导的胰腺转录组的特异性改变，这是组织修复和炎症的关键。 CCR2 是慢性炎症的重要介质，我们的初步研究支持了 MET 信号传导促进腺泡再生以应对酒精相关损伤的新假设，我们将在两个具体目标中进行测试。表明 MET 信号传导对于腺泡导管化生 (ADM) 是不可或缺的，这是腺泡细胞在损伤后恢复其数量的主要机制。为此，我们将使用一种新型的条件 MET 敲除小鼠特异性。对于成人腺泡细胞，保留导管和祖细胞，从而与离体 ADM 测定相结合，我们将检查 MET 在导致 ADM 的特定步骤中的作用，包括 a) 腺泡转分化为导管样上皮和/或 b)。随后化生上皮再分化为功能性腺泡细胞。在目标 2 中，我们将说明 MET 的缺失会增强 CCR2 介导的炎症反应，从而加剧酒精相关的损伤。我们将在酒精相关损伤的 MET 敲除模型中使用靶向药理学方法，研究 CCR2 信号传导在腺泡损伤中的作用，以及是否可以利用该信号传导促进腺泡更新。总的来说，我们的实验结果将揭示一种新的机制。 MET 在 ADM 和减少慢性炎症中的作用，这可能会导致有针对性的治疗，以促进因酒精相关损伤而导致的外分泌胰腺的修复。