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Drosophila and mouse models of PNPO deficiency

PNPO 缺乏症的果蝇和小鼠模型

基本信息

批准号：
10307547
负责人：
Xiaoxi Zhuang
金额：
$ 41.81万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307547
关键词：
Adult Affect Alleles Anatomy Animal Model Antiepileptic Agents Biochemical Biological Assay Birth Blood - brain barrier anatomy Brain Chemicals Child Coenzymes Data Defect Development Developmental Delay Disorders Diet Dominant-Negative Mutation Dopamine Drosophila genus Environment Environmental Risk Factor Enzymes Epilepsy Essential Genes Genes Genetic Histamine Homologous Gene Human International Knock-in Knock-in Mouse Knock-out Larva Lead Liver Cirrhosis Longevity Malnutrition Modeling Mus Mutation Neonatal Neurons Neurotransmitters Newborn Infant Other Genetics Patients Phenotype Point Mutation Proteins Pupa Pyridoxal Phosphate Pyridoxamine Pyridoxine 5 Phosphate Oxidase Reporting Role Seizures Serotonin Severities System Testing Transgenic Organisms Treatment outcome Vitamin B 6 Deficiency Vitamin B6 cell type cofactor cost effective dietary early onset epileptic encephalopathies fly functional disability gamma-Aminobutyric Acid gene interaction genetic manipulation human disease in vivo knock-down loss of function mutation mouse model mutant neural circuit neurochemistry neuromechanism

项目摘要

Abstract Pyridoxine 5'-phosphate oxidase (PNPO) is a rate-limiting enzyme in converting inactive forms of Vitamin B6 (VB6) in diet, including pyridoxine and pyridoxamine, to the only active form, pyridoxal 5'-phosphate (PLP). PLP is a cofactor required for the syntheses of dopamine, serotonin and GABA in the brain. In humans, PNPO deficiency is known to cause neonatal epileptic encephalopathy (NEE). Mutations in PNPO have been increasingly reported in NEE patients. Recent studies also identify PNPO as a contributor to early-onset epilepsies and one of the16 epilepsy genes involved in the common epilepsies. However, due to the lack of animal models, we know little about the developmental or adult functional impact of PNPO deficiency at systems, circuit or cellular level (e.g. involvement of GABA, dopamine or serotonin synthesis) under in vivo conditions. We know little about how mild PNPO deficiency interacts with other genetic defects or environmental factors (e.g. VB6 in diet) to cause seizures or other conditions. We have identified the Drosophila homolog of PNPO and identified a Drosophila mutant (sgll95 flies) with partial PNPO deficiency. Due to low PNPO activity, they are sensitive to dietary VB6 deficiency. We have since generated global knock-down as well as knock-in models in which the endogenous wild-type (WT) fly PNPO was replaced by human mutant PNPO found in patients. Viability during development, lifespan and seizure phenotype of these flies depend on the specific genetic manipulation as well as availability of VB6 in diet. We have also found that PNPO deficiency exacerbated other epileptic mutant alleles in flies with significant synergistic interactions. In Aim 1, we will define specific developmental stages in fly models in which PNPO deficiency leads to lethality and seizures. In Aim 2, we will define brain specific cell types involved in PNPO- deficiency-induced lethality and seizures in fly and mouse models. We will test gene-gene interactions (e.g., PNPO and other known epilepsy genes). In Aim 3, we will generate and characterize fly and mouse models that carry human PNPO mutations. 1

摘要