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.

摘要： 酒精相关性肝脏疾病（ALD）仍然是全球发病率和死亡率的主要原因。 目前，没有FDA批准的治疗方法可以阻断或逆转ALD进展。了解关键 促进ALD进展的步骤对于确定新的治疗靶点和减轻ALD的方法至关重要。 ALD。在导致ALD进展的因素中，突出的是酒精诱导的对肝脏的破坏。 肠屏障完整性，伴有微生物植物群失衡（生态失调）。这两种都能促进肠道和 肝损伤然而，过量饮酒引发生态失调的细胞/分子机制， 必须清楚地确定肠屏障完整性的损害。在这里，我们提出了独特的，令人兴奋的新数据， 表明慢性乙醇（EtOH）喂养破坏了肠道自噬，这是一种重要的细胞内分解代谢 一个始于自噬体（AV）形成的过程，自噬体（AV）隔离并传递衰老 大分子和细胞器到溶酶体在这个细胞器中分解。退化的物种是 通过合成补充。这种快速而持续的更替过程保存了所有人的专门功能。 细胞，但特别是肠细胞，它也调节肠道微生物组成，从而维持 肠道内稳态我们对自噬在保护肠屏障功能中的作用的理解已经取得了进展 但我们需要更好地了解EtOH滥用如何破坏肠道自噬以损害屏障 功能我们的目标是确定乙醇暴露在细胞中的自噬失调的机制。 肠细胞损害肠道屏障的完整性，并促进酒精诱导的肝损伤。我们建议 具体目标：目标1。研究EtOH诱导的溶酶体破坏如何影响上皮细胞屏障 目的2）阐明EtOH诱导的自噬破坏对潘氏细胞功能的影响，目的3） 确定乙醇诱导的肝损伤如何因肠自噬缺陷而加重，但因 自噬在肠道中重新激活。