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Molecular and Cellular Effects of Human Mutations in Cytochrome P450 Reductase

人类细胞色素 P450 还原酶突变的分子和细胞效应

基本信息

批准号：
8072565
负责人：
BETTIE SUE SILER MASTERS
金额：
$ 55.09万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-21 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8072565
关键词：
Address Adenoviruses Adult Affect Animal Model Antley-Bixler syndrome Bacterial Model Behavior Binding Biological Assay Categories Cell model Cell physiology Cells Characteristics Colon Carcinoma Coupled Cytochrome P450 Cytochromes b5 DNA Microarray Chip Defect Dependence Development Electron Transport Endoplasmic Reticulum Enzymatic Biochemistry Enzymes Event Film Flavins Fluorescence Fluorescence Spectroscopy Gene Expression Gene Expression Profiling Gene Mutation Genetic Polymorphism Heme High Pressure Liquid Chromatography Human Human Cell Line Intestines Kinetics Knock-out Knowledge Lead Liver Mammalian Cell Measures Mediating Messenger RNA Metabolic Metabolic Biotransformation Metabolism Methods Modeling Molecular Molecular Analysis Molecular Profiling Morphology Mus Mutate Mutation NADP NADPH-Ferrihemoprotein Reductase Oxidation-Reduction Oxygenases POR gene Phenotype Population Property Proteins Public Health Recombinants Research Residual state Signal Transduction Solutions Spectrum Analysis Structure Techniques Temperature Testing Therapeutic Therapeutic Agents Thermodynamics Time Tissues Titrations Transfection Transgenic Animals Untranslated Regions Variant Work X ray diffraction analysis X-Ray Crystallography X-Ray Diffraction Xenobiotics base bone bone cell cofactor cytochrome c design environmental agent falls intestinal epithelium knock-down mutant osteosarcoma oxidation physical property prenatal reconstitution research study response skeletal small hairpin RNA young adult

项目摘要

SUMMARY/ABSTRACT NADPH-cytochrome P450 oxidoreductase (CYPOR, encoded by the POR gene) deficiency has been correlated with the skeletal and steroidogenic anomalies of Antley-Bixler syndrome (ABS), although its specific effects on cytochrome P450 (CYP)-mediated xenobiotic and endobiotic metabolism remain unresolved. Forty naturally occurring human CYPOR variants, recently discovered and representing a broad range of residual activities, have been categorized based on phenotypic correlation and preliminary enzymology. This research plan is designed to address, on a molecular and cellular level, how naturally occurring POR mutations and polymorphic variations affect the structural arrangement and catalytic function of CYPOR in supporting cellular processes. Specific Aim 1 ¿ Molecular Analysis of POR Variants will examine the hypothesis that specific residues, when mutated, produce proteins with altered electron transport and/or oxidation/reduction partner interaction properties. To address this aim, both solution (spectroscopic, kinetic, and thermodynamic) and crystallographic (X-ray diffractions) techniques will be utilized. Preliminary evidence suggests that specific deficiencies may be addressable from a therapeutic perspective. Furthermore, CYPOR deficiency, as well as the subsequent imbalance of CYP metabolites, is predicted to result in altered gene expression profiles that lead to developmental defects. Therefore, Specific Aim 2 ¿ Cellular Analysis of Downstream Events in CYPOR Deficiency will utilize cellular models of tissues affected by varying degrees of CYPOR deficiency. To address this aim, defective POR genes will be introduced into both primary (isolated from POR[lox/lox] mouse tissues) and transformed human (liver, intestinal, and bone) cell models in order to measure the direct metabolic (CYP-mediated activity assays) and downstream response (functional assays and gene expression profiling) to xenobiotic/endobiotic challenge.

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