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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：
8428356
负责人：
Natalia Nieto
金额：
$ 40.68万
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/8428356
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 Injury 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 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 liver disease 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 liver disease result from the gut-to-liver interaction. Milk osteopontin protects the gut by maintaining the epithelial barrier function, providing mucosal defense, preventing sepsis and the inflammatory response. So far, a role for milk osteopontin in protecting from alcoholic liver disease has not been established. We believe that nutritional therapy using milk osteopontin could protect from alcohol-induced liver injury. In this Application we will focus on testing the Central Hypothesis "Dietary supplementation with milk osteopontin could prevent alcoholic liver disease due to its gut protective and antisteatotic actions". In particular, we hypothesize that 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. Using models of alcohol-induced liver injury, mice will be treated with milk osteopontin to assess its therapeutic potential. To prove our hypothesis we plan three Specific Aims. In Aim 1, we will analyze if milk osteopontin blocks 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 milk osteopontin blunts steatosis by targeting fatty acid metabolism; and second, we will dissect if the ability of milk osteopontin to bind lipopolysaccharide lowers Kupffer cell activation, TNF¿ production as well as other pro-inflammatory cytokines and oxidative/nitrosative stress. The chronic Lieber-DeCarli model along with dextran sodium sulfate or lipopolysaccharide treatment will be used. In Aim 3, a new model of alcoholic liver disease based on autophagy blockade will be developed. Next, we will identify if milk osteopontin reduces steatosis and liver injury by activating the autophagy pathway independent of targeting bacterial translocation or binding lipopolysaccharide. Thus, the Overall Goal of this Proposal is to investigate whether dietary administration of milk osteopontin could be an efficient low-cost therapeutic strategy for slowing down or preventing the progression of alcoholic liver disease. PUBLIC HEALTH RELEVANCE: Alcoholic liver disease affects several million people worldwide and progresses to alcoholic steatohepatitis, fibrosis and cirrhosis in many patients. We have recently identified osteopontin as a vitamin D-inducible protein with the ability to protect from alcohol-induced liver injury. The work proposed herein will evaluate and elucidate the mechanisms by which the protective effects of vitamin D and osteopontin occur; thus, contributing to design new, accessible and inexpensive therapies to prevent or slow down alcoholic hepatitis.

描述（由申请人提供）：酒精性肝病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。酒精性肝病的发生和进展的关键事件来自肠道-肝脏相互作用。牛奶骨桥蛋白通过维持上皮屏障功能、提供粘膜防御、预防脓毒症和炎症反应来保护肠道。到目前为止，牛奶骨桥蛋白在预防酒精性肝病中的作用尚未确定。我们认为，使用牛奶骨桥蛋白的营养疗法可以保护酒精引起的肝损伤。在本申请中，我们将集中于测试中心假设“膳食补充牛奶骨桥蛋白可以预防酒精性肝病，因为它具有肠道保护和抗脂肪变性作用”。特别是，我们假设牛奶骨桥蛋白将：1）靶向肠-肝轴，保护肠粘膜屏障，阻断革兰氏阴性菌从肠道移位至门静脉循环，从而降低脂多糖水平; 2）通过靶向脂肪酸代谢，预防脂肪变性和肝损伤以及减少脂多糖介导的枯否细胞活化和TNF？产生;以及3）通过增加自噬避免肝脂肪变性、炎症和肝损伤，自噬是最近确定的调节脂肪变性的途径。使用酒精诱导的肝损伤模型，将小鼠用牛奶骨桥蛋白治疗以评估其治疗潜力。为了证明我们的假设，我们计划三个具体目标。在目标1中，我们将分析牛奶骨桥蛋白是否阻断乙醇介导的肠道通透性增加、细菌移位和脂多糖可用性。将使用慢性Lieber-DeCarli模型沿着葡聚糖硫酸钠治疗。在目标2中，首先，我们将确定牛奶骨桥蛋白是否通过靶向脂肪酸代谢来减缓脂肪变性;其次，我们将分析牛奶骨桥蛋白结合脂多糖的能力是否降低枯否细胞活化、TNF？产生以及其他促炎细胞因子和氧化/亚硝化应激。将使用慢性Lieber-DeCarli模型沿着葡聚糖硫酸钠或脂多糖治疗。在目标3中，将开发基于自噬阻断的酒精性肝病新模型。接下来，我们将确定牛奶骨桥蛋白是否通过激活不依赖于靶向细菌移位或结合脂多糖的自噬途径来减少脂肪变性和肝损伤。因此，本提案的总体目标是研究牛奶骨桥蛋白的饮食管理是否可以成为减缓或预防酒精性肝病进展的有效低成本治疗策略。公共卫生关系：酒精性肝病影响全球数百万人，并在许多患者中进展为酒精性脂肪性肝炎、纤维化和肝硬化。我们最近发现骨桥蛋白是一种维生素D诱导的蛋白质，具有保护酒精诱导的肝损伤的能力。本文提出的工作将评估和阐明维生素D和骨桥蛋白的保护作用发生的机制;因此，有助于设计新的，可获得的和廉价的治疗方法来预防或减缓酒精性肝炎。