Novel Effects of Gravity on Intestinal Epithelial Barrier Responses to Alcohol

重力对肠上皮屏障对酒精反应的新影响

基本信息

批准号：
8136579
负责人：
Declan McCole
金额：
$ 21.6万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8136579
关键词：
3-Dimensional Acetaldehyde Address Affect Alcohol consumption Alcoholic Liver Diseases Alcohols Apical Bacteria Bathing Behavior Bioreactors Carbohydrates Cause of Death Cell Culture System Cell Culture Techniques Cell Death Cell Line Cell model Cell surface Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Collection Consultations Culture Media Cultured Cells D Cells Data Development Diffusion Dimensions Disease Endotoxins Environment Epithelial Epithelial Cells Event Exhibits Exposure to Fiber Force of Gravity Formalin Functional disorder Gases Gelatin Growth Health Human Human body Hypogravity Immune system Injury International Intestinal Content Intestines Investigation Knowledge Laboratories Life Style Lipopolysaccharides Liver Maintenance Measurement Measures Medical Membrane Microbe Microgravity Microscopy Modeling Molecular Target Monitor Nutrient Organ Pancreatitis Patients Perfusion Permeability Phase Phosphorylation Physiological Play Post-Translational Protein Processing Prevention strategy Process Property Proteins Regulation Resistance Role Scaffolding Protein Seeds Shapes Signaling Molecule Simulate State of Zero Gravity Structure Surface System Technology Temperature Testing Tight Junctions Time Tissues Toxic Actions Toxin Tube United States National Aeronautics and Space Administration Validation Vascular blood supply Western Blotting Width alcohol abuse therapy alcohol effect alcohol response alcohol use initiation base cell fixation cell growth cellular microvillus chronic alcohol ingestion density design experience gastrointestinal genetic regulatory protein in vivo insight intestinal epithelium macromolecule monolayer neuronal cell body novel novel therapeutics programs protein activation protein expression public health relevance research study response solute

项目摘要

DESCRIPTION (provided by applicant): Alcohol administration increases gastrointestinal permeability to bacteria and bacterial endotoxin (lipopolysaccharide (LPS)), and this plays a major role in the initiation of alcohol-induced tissue/organ damage in particular, alcoholic liver disease (ALD). Increased permeability appears to occur principally though the action of the toxic metabolite, acetaldehyde, on interepithelial tight junctions (TJ) that form a major component of the intestinal barrier. Therefore, understanding the underlying mechanisms by which alcohol promotes intestinal epithelial cell (IEC) permeability is important in designing strategies for the prevention or treatment of alcohol-associated medical disorders. In the human body, cells normally grow within a scaffolding of protein and carbohydrate fibers that help create a three dimensional (3-D) structure, thus allowing organs maintain their shape. Difficulties arise when studying cells on Earth as outside of the body, cells tend to grow in flat sheets and are not capable of duplicating the structure they normally hold. Therefore, a 3-D microgravity environment likely represents a more accurate cell culture model of epithelial behavior in vivo. Furthermore, the absence of the fundamental physical force of gravity on epithelial cell barrier function on board the ISS lends a unique opportunity to study the influence of gravity on cellular properties. We hypothesize that the influence of microgravity on the barrier properties of intestinal epithelial cells significantly modifies alcohol-induced effects on epithelial barrier function. We will test this hypothesis in the UH2 phase by (i) quantifying the effects of simulated microgravity on intestinal epithelial cell tight junction proteins and epithelial permeability; (ii) testing the effects of alcohol on barrier properties of IEC under simulated microgravity; (iii) optimizing a 3-dimensional cell culture system to study barrier function on board the ISS. In the UH3 phase we will (iv) quantify the effects of microgravity on IEC permeability induced by alcohol on board the ISS. These studies will provide a definitive answer as to what extent epithelial barrier function is influenced by gravity, and how this impacts upon epithelial responses to ingested toxins. As a result, we will provide new and fundamental knowledge that will likely have significant positive effects on human health, and allow the rational development of new therapeutic strategies for diseases associated with alcohol consumption and deficient intestinal barrier function. PUBLIC HEALTH RELEVANCE: From 2001-2005, there were approximately 79,000 deaths annually attributable to excessive alcohol use, the 3rd leading lifestyle-related cause of death for people in the U.S. each year (Centers for Disease Control). A major contributor to alcohol-induced disease is the ability of alcohol to compromise the normal barrier function of intestinal epithelial cells that line the gut. This project will utilize the unique zero- gravity environment of the International Space Station (ISS) to generate novel fundamental insights into the role of gravity in regulating intestinal barrier properties, and how the absence of gravity modifies the detrimental influence of alcohol on intestinal epithelial cell barrier function.

描述（由申请人提供）：饮酒会增加胃肠道对细菌和细菌内毒素（脂多糖（LPS））的通透性，这在酒精引起的组织/器官损伤，特别是酒精性肝病（ALD）中起重要作用。通透性增加似乎主要是通过有毒代谢物乙醛对上皮间紧密连接（TJ）的作用而发生的，而上皮间紧密连接是肠道屏障的主要组成部分。因此，了解酒精促进肠上皮细胞（IEC）通透性的潜在机制对于设计预防或治疗酒精相关疾病的策略非常重要。在人体内，细胞通常在蛋白质和碳水化合物纤维的支架内生长，有助于创建三维 (3-D) 结构，从而使器官保持其形状。研究地球上的细胞时会遇到困难，因为在体外，细胞往往以平板形式生长，并且无法复制它们通常具有的结构。因此，3D 微重力环境可能代表了体内上皮行为的更准确的细胞培养模型。此外，国际空间站上缺乏对上皮细胞屏障功能的基本物理重力，这为研究重力对细胞特性的影响提供了独特的机会。我们假设微重力对肠上皮细胞屏障特性的影响显着改变了酒精诱导的对上皮屏障功能的影响。我们将在 UH2 阶段通过以下方式检验这一假设：(i) 量化模拟微重力对肠上皮细胞紧密连接蛋白和上皮通透性的影响； (ii) 在模拟微重力下测试酒精对IEC阻隔性能的影响； (iii) 优化 3 维细胞培养系统以研究国际空间站上的屏障功能。在 UH3 阶段，我们将 (iv) 量化微重力对国际空间站上酒精引起的 IEC 渗透性的影响。这些研究将为重力对上皮屏障功能的影响程度以及重力如何影响上皮对摄入毒素的反应提供明确的答案。因此，我们将提供可能对人类健康产生重大积极影响的新的基础知识，并允许合理开发与饮酒和肠道屏障功能缺陷相关的疾病的新治疗策略。公共卫生相关性：从 2001 年到 2005 年，每年约有 79,000 人因过量饮酒而死亡，这是美国每年与生活方式相关的第三大死因（疾病控制中心）。酒精诱发疾病的一个主要原因是酒精会损害肠道内肠上皮细胞的正常屏障功能。该项目将利用国际空间站（ISS）独特的零重力环境，对重力在调节肠道屏障特性中的作用，以及重力缺失如何改变酒精对肠上皮细胞的有害影响产生新的基本见解。屏障功能。