Liver SVCT Systems: Vitamin C Uptake, Roles & Regulation

肝脏 SVCT 系统：维生素 C 摄取、作用

基本信息

批准号：
7787060
负责人：
JACK C REIDLING
金额：
$ 12.58万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7787060
关键词：
Alcoholic liver damage Antioxidants Ascorbic Acid Ascorbic Acid Deficiency Atherosclerosis Biochemical Reaction Biology Cardiovascular Diseases Cataract Cells Characteristics Clinical Connective Tissue Diseases Diabetes Mellitus Disease Fatty Liver Free Radical Scavengers Gall Bladder Diseases Genes Genetic Techniques Goals Grant Hepatitis Hepatocyte Histology Homeostasis Human Impaired wound healing In Vitro Investigation Kinetics Knock-out Knowledge Learning Liver Liver diseases Malignant Neoplasms Mammals Mediating Micronutrients Molecular Molecular Biology Mus Nature Nucleic Acid Regulatory Sequences Nutrient Pathology Patients Physiological Physiology Play Principal Investigator Process Protein Isoforms Regulation Relative (related person)Research Research Design Research Personnel Research Training Role Site Small Interfering RNA Sodium Source System Testing Tissues Training Vasomotor Vitamins Water-Soluble Vitamin Work base bone career career development clinically relevant clinically significant cofactor design human disease in vitro Model in vitro activity in vivo in vivo Model mouse model non-alcoholic problem drinker programs promoter protective effect sodium DEPENDENDENT vitamin C transporter 1 sodium-dependent vitamin C transporter 2 uptake

项目摘要

This proposal has been designed to advance the Principle Investigator (PI)towards his goal of academic independence. To attain that objective he will learn advanced molecular biology and mouse genetic techniques as well as liver pathology/histology in his studies of vitamin C regulation in the liver. Ascorbic acid (vitamin C) is a required essential micronutrient and effective antioxidant in humans. Two isoforms of the sodium-dependent vitamin C transporters (SVCT1 and SVCT2) are expressed in many human and mouse tissues, including the liver. Nothing is known regarding the regulation or relative contribution of the SVCT systems toward the overall vitamin C uptake process in the liver. Understanding these mechanisms is clinically relevant since many liver related diseases benefit from optimizing vitamin C body homeostasis. Our studies will use both an in vitro and in vivo approach to perform a comprehensive examination of the human liver vitamin C uptake process and regulation. We will determine the characteristics/kinetics of vitamin C uptake, characterize the hSVCTI and hSVCT2promoters, establish the relative contribution of hSVCTI and hSVCT2 towardtotal uptake using an siRNA approach and perform studies regardingthe effects of adaptive regulation of the vitamin C uptake process, all in human liver cells. In addition we will determine the characteristics/kinetics of vitamin C uptake in the liver of an in vivo mouse model that like humans is unable to synthesize vitamin C, establish the relative contribution of mSVCTI and mSVCT2 toward total uptake using the cre/lox system to generate liver specific knockouts of each gene independently, and continue our studies into adaptive regulation of vitamin C uptake in this in vivo model. Our studies into the mechanisms involved in maintaining and regulating normal vitamin C body homeostasis will potentially allow clinicians to develop effective strategies for patients during conditions of deficiency. The extensive training and educational opportunities will allow the PI to launch into a career as an independent academic researcher.

该建议旨在将主要研究者（PI）推向其学术目标独立。为了实现这个目标，他将学习高级分子生物学和小鼠遗传在肝脏中维生素C调节的研究中，技术以及肝脏病理学/组织学。抗坏血酸（维生素C）是人类必需的必需微量营养素和有效的抗氧化剂。两个同工型依赖钠的维生素C转运蛋白（SVCT1和SVCT2）在许多人和小鼠中表达组织，包括肝脏。关于SVCT的调节或相对贡献，尚无任何了解肝脏中整体维生素C摄取过程的系统。了解这些机制是临床相关，因为许多肝相关疾病受益于优化维生素C身体稳态。我们的研究将同时使用体外和体内方法对人进行全面检查肝脏维生素C摄取过程和调节。我们将确定维生素C的特征/动力学摄取，表征HSVCTI和HSVCT2启动器，建立HSVCTI和 HSVCT2使用siRNA方法截至摄取，并进行有关适应性影响的研究调节维生素C摄取过程，全部在人肝细胞中。此外，我们将确定体内小鼠模型的肝脏中维生素C摄取的特征/动力学，就像人类无法为了合成维生素C，建立MSVCTI和MSVCT2对总摄取的相对贡献使用CRE/LOX系统独立生成每个基因的肝脏特异性敲除，并继续我们的研究该体内模型中维生素C摄取的适应性调节。我们对机制的研究参与维持和调节正常维生素C身体体内平衡，可能会使临床医生能够在缺乏状态下为患者制定有效的策略。广泛的培训和教育机会将使PI成为独立学术研究员的职业。