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（由申请人证明）：肝病的主要原因是全球的肝脏疾病和肠道肝脏的肝病紧密的连接素，增强抗菌剂防御能力，维生素D靶向骨质蛋白使用维生素D和牛奶骨桥蛋白可能的肝损伤的治疗。从肠道到门户循环的革兰氏阴性bactoria降低了脂多糖水平；生产和3）避免肝脂肪变性。 AIM E中的AIM将分析维生素D和牛奶骨the骨是否会增加乙醇中的肠道渗透性，细菌易位和Opopopolysacharide的可用性。脂肪酸代谢和第二，如果骨桥蛋白结合脂多糖的能力降低了kupffer细胞的激活，我们将发病在AIM 3中，将使用其他促炎的细胞因子。因此，应用的总体目标是调查维生素D和牛奶骨桥蛋白的饮食效率是一种效率的低成本治疗策略，用于减慢或促进性肝炎。