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Functions of vitamin E and the tocopherol transfer protein

维生素 E 和生育酚转移蛋白的功能

基本信息

批准号：
10394948
负责人：
DANNY MANOR
金额：
$ 62.47万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-20 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394948
关键词：
Address Affinity Animal Behavior Antioxidants Area Binding Biochemistry Biological Biology Biophysics Brain Cell membrane Cells Cellular biology Cerebellum Cirrhosis Clinical Trials Dietary Component Dietary Fats Disease Epidemic Fatty Liver Fatty acid glycerol esters Fibrosis Free Radicals Future Gene Expression Gene Expression Profile Genetic Models Genetic Transcription Genomics Goals Health Health Promotion Hepatic Hepatocyte Heritability Homeostasis Human In Vitro Inflammation Lipid Peroxidation Lipids Lipoproteins Liver Liver diseases Mediating Membrane Membrane Proteins Molecular Mouse Protein Mutation Nervous System Trauma Nervous system structure Neuraxis Neurologic Neurologic Dysfunctions Nucleic Acids Nutrient Obesity Online Mendelian Inheritance In Man Organelles Organic Chemistry Organism Outcome Pathologic Pathology Patients Phosphatidylinositols Physiological Plants Play Process Proteins Research Risk Role Site Supplementation TTPA gene Testing Therapeutic Intervention Tissues Tocopherols Vertebrates Vitamin E Vitamin E Deficiency Vitamins alpha Tocopherol alpha-tocopherol transfer protein ataxia with vitamin E deficiency design dietary effective intervention human disease in vivo insight liver injury liver transplantation molecular imaging mouse model multidisciplinary nervous system disorder non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel prevent protein function protein transport severe injury trafficking trait transcription factor translational impact vesicle transport vitamin analog

项目摘要

Alpha-tocopherol (vitamin E) is an essential nutrient and the major fat-soluble antioxidant in humans. The most critical health-promoting action of vitamin E is thought to be anchored in protecting the central nervous system (CNS) from damage to membranes, proteins and nucleic acids induced by reactive species or free radicals. The levels and distribution of vitamin E in the body are regulated by hepatic alpha tocopherol transfer protein (TTP), which regulates secretion of the vitamin from the liver to circulating lipoproteins, and in turn to all tissues. Accordingly, mutations in the TTPA gene are the only known cause for ataxia with vitamin E deficiency (AVED; OMIM 277460). Our studies over the years have identified critical functions and mechanisms of action of a-tocopherol and TTP and we have made important discoveries that detail how TTP transports the vitamin across cells in the liver and the cerebellum. The proposed research will focus on three areas of critical importance: 1) we will decipher the molecular mechanisms underlying TTP-facilitation of trafficking of a- tocopherol from the endocytic compartment to the plasma membrane. 2) We will examine the molecular mechanisms and physiological consequences of novel, antioxidant independent activities of vitamin E, and their consequences on neurological health in a mouse model of vitamin E deficiency. 3) We will decipher the mechanisms by which vitamin E prevents the pathological progression of non alcoholic fatty liver disease to severe, irreversible liver disease (non alcoholic steatohepatitis). The results from our studies will provide important new insight into the role of vitamin E in health and disease.

α-生育酚(维生素E)是人体必需的营养物质，也是主要的脂溶抗氧化剂。维生素E最关键的健康促进作用被认为是保护中枢神经系统(CNS)免受活性物质或自由基引起的膜、蛋白质和核酸的损害。维生素E在体内的水平和分布受肝脏α-生育酚转移蛋白(TTP)的调节，TTP调节维生素E从肝脏分泌到循环脂蛋白，然后再分泌到所有组织。因此，TTPA基因突变是维生素E缺乏导致共济失调的唯一已知原因(AVED；OMIM 277460)。我们多年来的研究已经确定了α-生育酚和TTP的关键功能和作用机制，并取得了重要发现，详细说明了TTP如何通过肝脏和小脑的细胞转运维生素。这项拟议的研究将集中在三个至关重要的领域：1)我们将破译TTP促进α-生育酚从胞内转运到质膜的分子机制。2)我们将在维生素E缺乏的小鼠模型中研究维生素E的新的、抗氧化剂非依赖性活性的分子机制和生理后果，以及它们对神经健康的影响。3)我们将破译维生素E阻止非酒精性脂肪性肝病发展为严重的、不可逆转的肝病(非酒精性脂肪性肝炎)的机制。我们的研究结果将为维生素E在健康和疾病中的作用提供重要的新见解。