Role of Intestinal Autophagy in the Pathogenesis of Alcohol Associated Liver Disease

肠道自噬在酒精相关性肝病发病机制中的作用

• 批准号: 10566088
• 负责人: Paul Gideon Thomes
• 金额: $ 50.03万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10566088
• 关键词: Affect; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Aspirin; Attenuated; Autophagocytosis; Autophagosome; Biogenesis; Catabolic Process; Cell physiology; Cells; Chronic; Colon; Cytoplasm; Data; Disease Progression; Endotoxemia; Enzymes; Epithelial Cells; Epithelium; Ethanol; Exhibits; Extravasation; FDA approved; Functional disorder; GTF2H1 gene; Health; Heavy Drinking; Homeostasis; Impairment; Intestinal Mucosa; Intestinal permeability; Intestines; Investigation; Large Intestine; Leaky Gut; Liver diseases; Lysosomes; Methods; Mission; Molecular; Morbidity - disease rate; Muramidase; Mus; National Institute on Alcohol Abuse and Alcoholism; Nuclear; Organ; Organelles; Organoids; Paneth Cells; Pathogenesis; Process; Public Health; Research; Research Support; Risk Factors; Role; Small Intestines; Small intestine mucous membrane; Testing; alcohol effect; alcohol exposure; alcohol misuse; bactericide; dysbiosis; feeding; gastrointestinal epithelium; gut homeostasis; gut microbiota; insight; intestinal barrier; intestinal crypt; intestinal epithelium; liver function; liver injury; macromolecule; microbial composition; microbiota; mortality; novel; preservation; senescence; therapeutic target; transcription factor; treatment strategy

Abstract: Alcohol-Associated Liver Disease (ALD) continues to be a major cause of morbidity and mortality worldwide. Currently, there are no FDA-approved therapies that block or reverse ALD progression. Understanding the key steps that promote ALD progression is essential to identifying new treatment targets and methods that alleviate ALD. Prominent among the factors that contribute to ALD progression is the alcohol-induced disruption of intestinal barrier integrity, accompanied by microbial flora imbalance (dysbiosis). Both these promote gut and liver injury. However, the cellular/molecular mechanisms by which excessive drinking triggers dysbiosis and compromises intestinal barrier integrity must be clearly established. Here, we present unique, exciting new data, showing that chronic ethanol (EtOH) feeding disrupts intestinal autophagy, a crucial intracellular catabolic process that begins with the formation of autophagosomes (AV), which sequester and deliver senescent macromolecules and organelles to lysosomes for breakdown in this organelle. The degraded species are replenished by synthesis. This process of rapid and constant turnover preserves the specialized functions of all cells, but especially intestinal cells and it regulates intestinal microbial composition as well, thereby, maintaining gut homeostasis. Our understanding of autophagy’s role in preserving intestinal barrier function has progressed significantly, but we need a better understanding of how EtOH misuse disrupts gut autophagy to impair barrier function. Our objective is to ascertain the mechanism(s) by which EtOH exposure dysregulates autophagy in intestinal cells to compromise gut barrier integrity and promotes alcohol-induced liver injury. We propose the following Specific Aims: Aim 1. Investigate how EtOH-induced lysosome disruption affects epithelial cell barrier integrity; Aim 2) Clarify the effects of EtOH-induced autophagy disruption on Paneth cell function and Aim 3) Ascertain how EtOH-induced liver injury is exacerbated by deficient intestinal autophagy but is alleviated by autophagy reactivation in the gut.

抽象的： 酒精相关性肝病 (ALD) 仍然是全世界发病和死亡的主要原因。 目前，尚无 FDA 批准的疗法可以阻止或逆转 ALD 进展。 促进 ALD 进展的步骤对于确定新的治疗目标和方法至关重要 导致 ALD 进展的重要因素是酒精引起的 ALD 破坏。 肠道屏障完整性，伴随着微生物菌群失衡（生态失调）。 然而，过量饮酒引发菌群失调的细胞/分子机制。 必须明确确定损害肠道屏障完整性的因素，在这里，我们提出了独特的、令人兴奋的新数据， 研究表明，长期摄入乙醇（EtOH）会破坏肠道自噬，这是一种重要的细胞内分解代谢 这个过程始于自噬体 (AV) 的形成，它隔离并传递衰老细胞 大分子和细胞器进入溶酶体，在该细胞器中分解。 这种快速而持续的周转过程保留了所有的特殊功能。 细胞，特别是肠道细胞，它还调节肠道微生物组成，从而维持 我们对自噬在保护肠道屏障功能中的作用的理解已经取得进展。 显着，但我们需要更好地了解乙醇滥用如何破坏肠道自噬从而损害屏障 我们的目标是确定乙醇暴露导致自噬失调的机制。 肠道细胞会损害肠道屏障的完整性并促进酒精引起的肝损伤。 具体目标如下： 目标 1. 研究乙醇诱导的溶酶体破坏如何影响上皮细胞屏障 完整性；目标 2) 阐明乙醇诱导的自噬破坏对潘氏细胞功能的影响和目标 3) 确定肠道自噬缺陷如何加剧 EtOH 诱导的肝损伤，而通过以下方式减轻肝损伤： 肠道中的自噬重新激活。