Pancreatic Regeneration from Alcohol-Associated Injury

酒精相关损伤的胰腺再生

• 批准号: 9123513
• 负责人: Lisa A. Elferink
• 金额: $ 18.41万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9123513
• 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; Genetic; Health; Human; Inflammation; Inflammation Mediators; Inflammatory Response; Injury; Knock-out; Knockout Mice; Knowledge; Link; MET gene; Mediating; Mediator of activation protein; Metaplasia; Metaplastic; Modeling; Mus; Natural regeneration; Pancreas; Pancreatic Injury; Pancreatitis; Population; Process; Research; Risk Factors; Role; Secretory Cell; Signal Transduction; Specimen; Stem cells; Testing; Tissues; Up-Regulation; alcohol effect; alcohol exposure; alcohol response; alcohol-related injury; chemokine receptor; chronic pancreatitis; design; feeding; injured; macrophage; meetings; novel; progenitor; repaired; research study; response; self-renewal; stem; symptomatology; targeted treatment; tissue repair; transcriptome; 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（由适用提供）：高酒精摄入量与坏死性疾病（例如胰腺炎）之间的关联已有100多年的历史。然而，只有5％的重饮酒者患上胰腺炎，这意味着存在与酒精相关损伤后恢复胰组织的适应性机制。值得注意的是，酒精相关损伤后胰腺修复和再生至关重要的机制尚未完全分析或完全理解。这项拟议的研究旨在表征对于胰腺腺泡细胞再生至关重要的机制，这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）作为腺泡细胞的内在生存和/或修复机制的重要性。我们的研究表明，正常的成年胰腺中MET信号传导低。然而，人类胰腺炎标本中的导管和腺泡细胞中的MET水平升高，这与Met作为自适应修复机制的作用一致。我们还表明，成年鼠腺泡细胞中MET的遗传缺失与腺泡细胞凋亡增加有关，慢性炎症与酒精相关损伤后纤维化伴有纤维化。值得注意的是，我们还发现缺乏的酒精喂养小鼠有广泛的导管化生，这是通过茎/祖细胞群扩展而可能的。最后，我们确定了在酒精相关损伤期间通过MET信号传导介导的胰腺转录组的特异性变化，这是组织修复和感染的关键。值得注意的是，MET信号传导的丧失导致CCR2的上调，CCR2是慢性感染的重要介体。我们的初步研究支持了新的假设，即MED信号传导促进腺泡的再生，以响应与酒精相关的损伤。该假设将以两个具体的目的进行检验。在AIM 1中，我们将证明MET信号传导对于腺泡 - 导管化生（ADM）是必不可少的，这是腺泡细胞在损坏后恢复其数量的主要机制。为此，我们将使用针对成年腺泡细胞的新型有条件的敲除小鼠，从而使导管和祖细胞与离体ADM分析相结合。我们将检查MET在导致ADM的特定步骤中的作用，包括A）腺泡的跨性别分化为导管样上皮和/或b）随后将化生性上皮菌的分化重新分化为功能性酸性细胞。在AIM 2中，我们将说明MET的丧失会增强CCR2介导的炎症反应，从而加剧与酒精相关的损伤。在我们的大都会酒精相关损伤的MET基因敲除模型中，我们将使用靶向药物方法，研究CCR2信号在腺泡损伤中的作用，以及是否可以利用该信号传导来促进腺泡续订。总体而言，我们的实验结果将发现MET在ADM和减少慢性感染中的新作用，这可能导致靶向治疗以促进由于酒精相关损伤而促进外分泌胰腺的修复。