Genetic Analysis of Copper Toxicity Mechanisms in iPSC-derived Human Neurons

iPSC 衍生的人类神经元铜毒性机制的遗传分析

基本信息

批准号：
8762863
负责人：
Victor Faundez
金额：
$ 19.27万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8762863
关键词：
Address Affect Alleles Alzheimer&apos s Disease Axon Binding Proteins Biochemical Reaction Biological Brain Brain Pathology Brain-Derived Neurotrophic Factor Cell Survival Cells Childhood Copper Cutis Laxa Defect Dendrites Disease Disease Attributes Dopamine-beta-monooxygenase Enzymes Extracellular Matrix Proteins Fibroblasts Figs - dietary Generations Genes Genetic Golgi Apparatus Hepatolenticular Degeneration Hereditary Disease Homeostasis Human Hypopigmentation In Vitro Knowledge Lead Link Liver Failure Membrane Menkes Kinky Hair Syndrome Metabolism Micronutrients Monophenol Monooxygenase Mutation Nerve Degeneration Neurobiology Neurodegenerative Disorders Neurologic Neurons Neuropeptides Neurotransmitters Null Lymphocytes Organ Organelles Organism Oxidants Pathology Pathway interactions Patients Phenotype Pigments Protein-Lysine 6-Oxidase Proteins Proteome Research Severities Skin Source Starvation Testing Tissues Toxic effect copper-binding protein crosslink disease phenotype genetic analysis genetic pedigree induced pluripotent stem cell loss of function melanocyte member mutant neurotrophic factor peptidylglycine alpha-amidating monooxygenase polypeptide protein function public health relevance secretory protein therapeutic development trafficking

项目摘要

DESCRIPTION (provided by applicant): Copper is a powerful toxic oxidant for neurons whose free levels must be tightly controlled. It is also an essential micronutrient necessary for neurona enzymatic reactions, such as neurotransmitter and neuropeptide synthesis. The importance of copper to neuronal cells is illustrated by Menkes disease, an X-linked genetic disorder characterized by neuronal tissue copper starvation, altered neuronal polarity, and cell survival phenotypes. The precise cellular mechanisms underlying these copper- dependent neuronal phenotypes remain unknown and constitute the focus of this application. The gene affected in Menkes disease, ATP7A, is a Golgi localized protein that loads copper into secretory proteins. This fact suggests that Menkes disease phenotypes result from alterations in the entire copper sensitive secreted proteome. We propose to test this hypothesis by comprehensively identifying the human neuronal copper-sensitive secreted proteome in human induced pluripotent stem cells (iPSCs) differentiated into neurons. We will test the participation of the copper-sensitive proteome in the progression and severity of Menkes disease neuronal pathology. Such knowledge will contribute to our understanding and development of therapeutics in Menkes disease as well as diseases affected by copper availability, such as Alzheimer's disease.

描述（由申请人提供）：铜是必须严格控制自由水平的神经元的强大有毒氧化剂。它也是神经酶促反应（例如神经递质和神经肽合成）所需的必不可少的微量营养素。铜对神经元细胞的重要性由Menkes病（一种以神经元组织铜饥饿，神经元极性改变和细胞存活表型为特征的X连锁遗传疾病。这些铜依赖的神经元表型背后的精确细胞机制仍然未知，构成了该应用的重点。在Menkes病ATP7A中受影响的基因是一种高尔基体局部蛋白，可将铜载入分泌蛋白。这一事实表明，Menkes疾病表型是由整个铜敏感分泌蛋白质组的改变引起的。我们建议通过全面识别人类诱导的多能干细胞（IPSC）中的人类神经铜敏感的分泌蛋白质组（IPSC）来检验这一假设。我们将测试铜敏感蛋白质组参与MENKES病神经元病理的进展和严重程度。这种知识将有助于我们对Menkes疾病中治疗剂的理解和发展以及受铜可用性影响（例如阿尔茨海默氏病）的疾病。