Milk osteopontin, a nutritional therapeutic intervention for alcoholic hepatitis

牛奶骨桥蛋白，酒精性肝炎的营养治疗干预措施

基本信息

批准号：
8549929
负责人：
Natalia Nieto
金额：
$ 37.83万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-25 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8549929
关键词：
Acute Adrenal Cortex Hormones Adult Affect Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Anti-Inflammatory Agents Anti-inflammatory Autophagocytosis Bacteria Bacterial Translocation Binding Blood Blood Circulation Body Fluids Cells Cessation of life Chronic Cirrhosis Clinical Trials Data Diet Dietary Supplementation Disease Progression Epithelial Ethanol Ethanol toxicity Event Fatty Liver Fibrosis Goals Gram-Negative Bacteria Hemorrhage Hepatocyte Host Defense Human Milk Immune Impairment Incidence Indium Infant Infection Inflammation Inflammatory Inflammatory Response Intervention Intestines Knockout Mice Kupffer Cells Lead Link Lipid Binding Lipid Peroxidation Lipopolysaccharides Liver Liver diseases Malnutrition Mediating Messenger RNA Milk Modeling Mus Nutritional Nutritional Support Outcome Pathway interactions Patients Permeability Phagocytosis Plasma Production Proteins Role Sepsis Sodium Dextran Sulfate Steatohepatitis Supplementation TNF gene Testing Therapeutic Therapeutic Intervention Tight Junctions Tissues Transgenic Mice Translational Research Umbilical cord structure Up-Regulation Vitamin D Vitamin D Deficiency Wild Type Mouse Work antimicrobial base cost cytokine design fatty acid metabolism feeding gastrointestinal improved in vivo Model inhibition of autophagy liver injury macrophage mortality mouse model novel therapeutic intervention osteopontin outcome forecast overexpression pathogen prevent problem drinker promoter protective effect protein expression response

项目摘要

DESCRIPTION (provided by applicant): Alcoholic hepatitis is a leading cause of liver disease and death worldwide; thus, there is an urgent need to develop novel therapeutic interventions. Key events for the onset and progression of alcoholic hepatitis result from the gut-to-liver interaction. Vitamin D deficiency is highly prevalent in patients with alcoholic hepatitis. VitaminD supplementation regulates the expression of tight junction proteins, enhances antimicrobial defenses and reduces proinflammatory cytokines in the gut. Vitamin D targets osteopontin via a vitamin D-responsive element in the osteopontin promoter. Milk osteopontin protects the gut by maintaining the epithelial barrier function, providing mucosal defense, preventing sepsis and the inflammatory response. So far, a link between vitamin D and osteopontin in protecting from alcoholic hepatitis has not been established. We believe that nutritional therapy using vitamin D and milk osteopontin could protect from alcohol-induced liver injury. In this Application we will focus on testing the Central Hypothesis "Dietary supplementation with vitamin D or milk osteopontin could prevent alcoholic hepatitis due to the gut protective and antisteatotic actions of osteopontin". In particular, we hypothesize that vitamin D and milk osteopontin will: 1) Target the gut-liver axis protecting the intestinal mucosal barrier and blocking the translocation of Gram-negative bacteria from the gut into the portal circulation thus lowering lipopolysaccharide levels; 2) Prevent steatosis and liver injury by targeting fatty acid metabolism and decreasing lipopolysaccharide-mediated Kupffer cell activation and TNF¿ production; and 3) Avert hepatic steatosis, inflammation and liver injury by increasing autophagy, a recently identified pathway regulating steatosis. We will develop new in vivo models of alcoholic hepatitis to further our understanding of the mechanisms of liver injury. Using these models, mice will be treated with vitamin D or milk osteopontin to assess their therapeutic potential. To prove our hypothesis we plan three Specific Aims. In Aim 1, we will analyze if vitamin D and milk osteopontin block the ethanol-mediated increase in gut permeability, bacterial translocation and lipopolysaccharide availability. The chronic Lieber-DeCarli model along with dextran sodium sulfate treatment will be used. In Aim 2, first, we will determine whether vitamin D and milk osteopontin blunt steatosis by targeting fatty acid metabolism; and second, we will dissect if the ability of osteopontin to bind lipopolysaccharide lowers Kupffer cell activation, TNF¿ production as well as other pro-inflammatory cytokines. The chronic Lieber-DeCarli model along with dextran sodium sulfate or lipopolysaccharide treatment will be used. In Aim 3, a new model of alcoholic hepatitis based on autophagy blockade will be developed. Next, we will identify if vitamin D and milk osteopontin reduce steatosis by activating the autophagy pathway independent of targeting bacterial translocation or binding lipopolysaccharide. Thus, the Overall Goal of this Application is to investigate whether dietary administration of vitamin D and milk osteopontin could be an efficient low-cost therapeutic strategy for slowing down or preventing the progression of alcoholic hepatitis.

描述（由适用提供）：酒精性肝炎是全球肝病和死亡的主要原因；因此，迫切需要开发新的治疗干预措施。酒精性肝炎发作和进展的关键事件是肠道相互作用引起的。维生素D缺乏症在酒精性肝炎患者中非常普遍。维生素补充可调节紧密连接蛋白的表达，增强抗菌防御并减少肠道中促炎的细胞因子。维生素D通过骨桥蛋白启动子中的维生素D反应元件靶向骨桥蛋白。牛奶骨桥蛋白通过保持上皮屏障功能，提供粘膜防御，防止败血症和炎症反应来保护肠道。到目前为止，尚未建立维生素D和骨桥蛋白在保护酒精性肝炎方面的联系。我们认为，使用维生素D和牛奶骨桥蛋白的营养疗法可以防止酒精诱发的肝损伤。在此应用中，我们将专注于测试中心假设：“补充维生素D或牛奶骨桥蛋白可以防止由于肠道保护和抗抗脑桥蛋白而预防酒精性肝炎”。特别是，我们假设维生素D和牛奶骨桥蛋白将：1）针对保护肠道粘膜屏障的肠道轴，并阻止革兰氏阴性细菌从肠道易位，从肠道进入门肠循环，从而降低脂多糖水平； 2）通过靶向脂肪酸代谢并减少脂多糖介导的库普弗细胞激活和TNF的产生来预防脂肪变性和肝损伤； 3）通过增加自噬来避免肝脂肪变性，感染和肝损伤，这是一种最近确定的途径调节脂肪变性。我们将开发新的酒精性肝炎体内模型，以进一步了解肝损伤机制。使用这些模型，将用维生素D或牛奶骨桥蛋白治疗小鼠，以评估其治疗潜力。为了证明我们的假设，我们计划三个具体目标。在AIM 1中，我们将分析维生素D和牛奶骨桥蛋白是否阻止乙醇介导的肠道通透性，细菌易位和脂多糖的可用性增加。将使用慢性lieber-decarli模型以及硫酸钠处理。在AIM 2中，首先，我们将通过靶向脂肪酸代谢来确定维生素D和牛奶骨桥骨钝性脂肪变性是否；其次，我们将剖析骨桥蛋白结合脂多糖的能力是否降低了库普弗细胞的激活，TNF？产生以及其他促炎性细胞因子。将使用慢性lieber-decarli模型以及硫酸钠或脂多糖处理。在AIM 3中，将开发一种基于自噬阻滞的酒精性肝炎的新模型。接下来，我们将通过激活独立于靶向细菌易位或结合脂多糖的自噬途径来确定维生素D和牛奶骨桥蛋白是通过激活自噬途径来减少脂肪变性的。这是该应用的总体目标是研究饮食中维生素D和牛奶骨桥蛋白的饮食是否可能是有效的低成本治疗策略，可减缓或防止酒精性肝炎的进展。