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New Vistas in Vitamin K Metabolism

维生素 K 代谢的新前景

基本信息

批准号：
9031119
负责人：
Allan Edward Rettie
金额：
$ 28.63万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-05 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9031119
关键词：
Adopted Affect Anabolism Anticoagulants Automobile Driving Biochemical Biochemical Reaction Biological Biological Assay Blood coagulation CYP4F11 gene Cancer Patient Catabolism Cell Line Cell model Cells Chemicals Chronic Kidney Failure Cytochrome P450 Data Development Diet Dimethylallyltranstransferase Engineering Enzymatic Biochemistry Enzymes Event Extrahepatic Factor IX Fat-Soluble Vitamin Foundations Fracture Future Genes Genetic Genetic Variation Genotype Goals Hand Health Hemostatic function HepG2 Hepatic Hepatocyte Homeostasis Human Hydroquinones Hydroxylation Individual Knowledge Label Laboratories Link Liver Mass Spectrum Analysis Measures Metabolic Metabolism Mixed Function Oxygenases Nutrient Oral Pathway interactions Patients Pharmacogenetics Physiological Population Process Production Proteins RNA Interference Recombinants Research Research Proposals Risk Risk Factors Role Sampling Series Side Source Supplementation Systems Analysis Testing Therapeutic Tissues Transfection Tumor Suppressor Genes Variant Vascular calcification Vitamin K Vitamin K 1 Vitamin K 2 Vitamin K Deficiency Warfarin analog base bone health bone metabolism calcification cancer therapy carboxylate carboxylation cell growth regulation cellular engineering cofactor combat coronary artery calcification dietary constituent enzyme activity genetic variant human tissue in vivo inhibitor/antagonist insight interest men mutant novel response soft tissue tool

项目摘要

DESCRIPTION (provided by applicant): The long-term aim of this research is to define the network of integrated metabolic events that underlie vitamin K anabolism and catabolism, in order to understand inter-subject variability in response to this essential dietary nutrient. In ths new application, we will establish the P450 enzymes, CYP4F2 and CYP4F11 as the key vitamin K hydroxylases that initiate catabolism of this essential dietary constituent. In addition, we will determine the role of the newly identified human UBDIA1 enzyme in the interconversion of vitamins K1 and K2. These efforts will establish the link between the core vitamin K cycle proteins and ancillary enzymes that modulate the availability of the hydroquinone cofactors that drive Gla protein production. Because there is a high degree of inter-individual variability in response to supplementation with vitamin K in highly vulnerable K-deficient populations (e.g. those suffering from chronic kidney disease, cancer patients), these studies are of high significance. The goals of this research proposal are three-fold, (i) to establish the relative roes of human CYP4F2 and CYP4F11 in the initiation of vitamin K catabolism, (ii) to establish the role and chemical mechanism of action of UBIAD1 in conversion of vitamin K 1 to K2 (MK-4), and (iii) to ascertain the influence of common genetic variation in each of these three genes on vitamin K homeostatis in human tissues and cellular models of increasing complexity, as a precursor to future in vivo studies. In preliminary studies, we have accomplished the important tasks of heterologous expression of each of the three target enzymes, and development of highly sensitive and specific tandem MS assays for analysis of vitamin K in a variety of biological matrices. With these tools in hand, we propose, in Aim1, to evaluate the roles of CYP4F2 and CYP4F11 in vitamin K catabolism. In Aim 2, we will express and purify human UBIAD1 to enable an unambiguous assessment of the enzyme's catalytic capability and chemical mechanism for conversion of vitamin K1 to K3. In Aim 3, we will use banked, genotyped human liver tissue and a novel engineered cell system for analysis of Gla protein production to determine the effect of common genetic variation in these newly described vitamin K cycle-associated genes on cellular vitamin K homeostasis.

描述（由申请人提供）：本研究的长期目标是确定维生素K合成代谢和分解代谢背后的综合代谢事件网络，以便了解对这种必需膳食营养素的反应的主体间变异性。在这个新的应用中，我们将建立P450酶，CYP4F2和CYP4F11作为关键的维生素K羟化酶，启动这一必需膳食成分的分解代谢。此外，我们将