Neurodegenerative consequences of PanK2 mutations

PanK2 突变的神经退行性后果

基本信息

批准号：
7216264
负责人：
PAUL T KOTZBAUER
金额：
$ 17.6万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-15 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7216264
关键词：
4&apos -phosphopantetheine Acetyl Coenzyme A Active Sites Acyl Carrier Protein Age Allosteric Regulation Alzheimer&apos s Disease Antibodies Antioxidants Basal Ganglia Behavioral Biochemical Biochemistry Biological Assay Brain Brain region Cell Culture System Cell Fractionation Cell Line Cell physiology Cells Cessation of life Characteristics Citric Acid Cycle Coenzyme A Cognition Complex Critical Pathways Cultured Cells Disease Disruption Doctor of Philosophy Environmental Risk Factor Enzymes Esters Fatty Acids Frameshift Mutation Functional disorder Gene Mutation Gene Targeting Generations Genes Genetic Globus Pallidus Goals Half-Life Human Human Cell Line Hydrogen Peroxide Impairment In Vitro Iron Knock-out Knockout Mice Label Lead Link Localized Lysine Lysophospholipids Mediating Metabolism Mitochondria Mouse Cell Line Movement Movement Disorders Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurologist Neurons Nonsense Codon Numbers Oxidative Stress Palmitoyl Coenzyme A Pantothenate kinase Parkinson Disease Pathogenesis Pathologic Pattern Phosphorylation Physiologic pulse Plasmid Cloning Vector Point Mutation Population Predisposition Prevalence Process Production Property Prosthesis Proteins Proteolytic Processing Pulse taking Pyruvate Dehydrogenase Complex Radio Radiolabeled Recombinant Proteins Recombinants Regulation Research Research Project Grants Resistance Role Scientist Small Interfering RNA Societies Speech Staining method Stains Structure Substantia nigra structure System Thioctic Acid Vitamins Work cell injury cofactor cost embryonic stem cell experience homologous recombination inhibitor/antagonist insight motor deficit mutant neuron loss null mutation pantothenate protein function radiotracer research study response skills synuclein uptake

项目摘要

DESCRIPTION (provided by applicant): The candidate is an M.D./Ph.D neurologist who is currently a trainee in the Center for Neurodegenerative Disease Research. His goal is to develop additional research skills and experience needed to become an independent clinician scientist working to understand the pathogenesis of neurodegenerative diseases. The proposed research project focuses on neurodegeneration with brain iron accumulation (NBIA), which causes progressive impairment of speech, movement and cognition. At the neuropathological level, NBIA is characterized by iron accumulation, inclusion formation, signs of oxidative stress, and death of multiple neuronal populations. These features are also seen to varying degrees in other neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Mutations in the gene for pantothenate kinase 2 (PanK2) were recently identified in a subset of NBIA cases. The PanK2 gene encodes an enzyme involved in coenzyme A (CoA) synthesis, a critical pathway linked to a number of cellular processes, including fatty acid synthesis, energy production, and possibly, synthesis of anti-oxidant molecules. The long term objectives of this project are to understand how PanK2 mutations lead to iron accumulation, oxidative stress, inclusion formation, and neuronal death. The proteolytic processing, mitochondrial localization and in vitro catalytic properties will by characterized for mutant Pank2 proteins and compared to the wild type human PanK2 protein. Cell culture systems will be established in which PanK2 expression is eliminated and in which wild type or mutant PanK2 proteins are over-expressed. Mice that lack PanK2 expression will also be generated. Cell lines and mice lacking PanK2 expression will be examined for changes in levels of biochemical intermediates hypothesized to be dependent on PanK2 function. Finally, neuronal and non-neuronal cells lacking PanK2 will be examined for signs of increased oxidative stress, susceptibility to oxidative injury, cellular and mitochondrial import of radio labeled iron, and inclusion formation.

描述（由申请人提供）：候选人是M.D./PH.D神经科医生，目前是神经退行性疾病研究中心的实习生。他的目标是发展额外的研究技能和经验，成为一名独立的临床医生，旨在了解神经退行性疾病的发病机理。拟议的研究项目侧重于脑铁的积累（NBIA），这会导致语音，运动和认知的逐渐损害。在神经病理学水平上，NBIA的特征是铁的积累，纳入形成，氧化应激的迹象以及多个神经元种群的死亡。这些特征在其他神经退行性疾病（包括帕金森氏病和阿尔茨海默氏病）中也有所不同。在NBIA病例的一部分中，最近发现了泛素激酶2（PANK2）的基因突变。 PANK2基因编码参与辅酶A（COA）合成的酶，这是与许多细胞过程相关的关键途径，包括脂肪酸合成，能量产生，可能是抗氧化剂分子的合成。该项目的长期目标是了解Pank2突变如何导致铁的积累，氧化应激，包容形成和神经元死亡。蛋白水解加工，线粒体定位和体外催化特性将以突变型Pank2蛋白的特征，并与野生型人Pank2蛋白进行比较。将建立消除PANK2表达的细胞培养系统，并在其中野生型或突变体Pank2蛋白过度表达。缺乏pank2表达的小鼠也将产生。将检查缺乏PANK2表达的细胞系和小鼠，以了解假设依赖PANK2功能的生化中间体水平的变化。最后，将检查缺乏PANK2的神经元和非神经元细胞，以了解氧化应激增加，氧化损伤的易感性，无线电标记的铁的细胞和线粒体进口的易感性以及纳入形成。