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

• 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
• 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

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）：饮酒会增加对细菌和细菌内毒素（脂多糖（LPS））的胃肠道通透性，这在饮酒诱导的组织/器官损害的开始，尤其是酒精性肝病（ALD）。尽管有毒代谢产物乙醛在上皮间紧密连接（TJ）上的作用主要是在主要发生的，而渗透率的提高似乎是发生的。因此，了解酒精促进肠道上皮细胞（IEC）渗透性的潜在机制对于设计预防或治疗与酒精相关的医疗疾病的策略很重要。在人体中，细胞通常在蛋白质和碳水化合物纤维的脚手架内生长，这些纤维有助于创建三维（3-D）结构，从而使器官保持其形状。当在人体外部研究细胞时会出现困难，细胞倾向于在平坦的床单中生长，并且无法复制它们通常保持的结构。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，ISS上没有重力对上皮细胞屏障功能的基本物理力为研究重力对细胞性质的影响提供了独特的机会。我们假设微重力对肠上皮细胞的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。我们将通过（i）量化模拟微重力对肠上皮细胞紧密连接蛋白和上皮渗透性的影响来检验这一假设； （ii）测试酒精对模拟微重力下IEC屏障特性的影响； （iii）优化3维细胞培养系统以在ISS上研究屏障功能。在UH3阶段，我们（IV）将量化微重力对ISS酒精引起的IEC渗透性的影响。这些研究将提供一个确定的答案，即上皮屏障功能受重力的影响，以及这如何影响对摄入的毒素的上皮反应。结果，我们将提供新的和基本的知识，这些知识可能会对人类健康产生重大积极影响，并允许合理发展与饮酒和肠道屏障功能不足有关的疾病的新治疗策略。 公共卫生相关性：从2001 - 2005年开始，每年大约有79,000人死亡归因于过度使用酒精，这是美国每年与生活方式有关的第三次领先生活方式有关的死亡原因（疾病控制中心）。饮酒引起的疾病的主要原因是酒精能够损害肠道上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（ISS）来产生对重力在调节肠道屏障特性中作用的新基本见解，以及缺乏重力如何改变酒精对肠道上皮上皮屏障功能的有害影响。