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

• 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
• 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' 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

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）：铜是一种强大的有毒氧化剂，神经元的游离水平必须严格控制。它也是神经细胞酶促反应所必需的微量营养素，如神经递质和神经肽的合成。Menkes病是一种x连锁遗传疾病，以神经元组织铜缺乏、神经元极性改变和细胞存活表型为特征，说明了铜对神经元细胞的重要性。这些依赖铜的神经元表型背后的精确细胞机制仍然未知，并构成了这一应用的焦点。受门克斯病影响的基因ATP7A是一种高尔基体定位蛋白，它将铜装载到分泌蛋白中。这一事实表明，门克斯病的表型是由整个铜敏感分泌蛋白质组的改变引起的。我们建议通过全面鉴定分化为神经元的人诱导多能干细胞（iPSCs）中的人神经元铜敏感分泌蛋白组来验证这一假设。我们将测试铜敏感蛋白组在Menkes病神经病理进展和严重程度中的参与。这些知识将有助于我们理解和开发门克斯病以及受铜可用性影响的疾病（如阿尔茨海默病）的治疗方法。