Tissue-specific pathways of copper homeostasis in growth and development

生长和发育过程中铜稳态的组织特异性途径

• 批准号: 8725649
• 负责人: MICHAEL J. PETRIS
• 金额: $ 40.98万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725649
• 关键词: ATP phosphohydrolase; ATP7A protein; Address; Alzheimer' s Disease; Area; Ataxia; Biological Process; Blood; Breast Epithelial Cells; Cardiovascular Diseases; Cations; Cell membrane; Chemotherapy-Oncologic Procedure; Child; Childhood; Connective Tissue; Connective Tissue Diseases; Copper; Data; Defect; Development; Dietary Copper; Disease; Embryo; Enzymes; Epithelial Cells; Equilibrium; Exhibits; Family; Functional disorder; Gastrointestinal tract structure; Gene Mutation; Goals; Golgi Apparatus; Growth; Growth and Development function; Health; Hepatic; Hepatocyte; Histocompatibility Testing; Homeostasis; Horns; Human; Hypopigmentation; Intake; Intestines; Knock-out; Knowledge; Lactation; Liver; Location; Mammary gland; Mediating; Menkes Kinky Hair Syndrome; Milk; Modeling; Molecular; Motor Neuron Disease; Motor Neurons; Mus; Mutation; Neonatal; Nerve Degeneration; Neurons; Nutrient; Nutritional Requirements; Organ; Pathogenesis; Pathway interactions; Patients; Peripheral; Physiology; Positioning Attribute; Pregnancy; Process; Reporting; Resistance; Role; Seizures; Source; Staging; Stream; Syndrome; Testing; Tissues; bactericide; base; cell type; chemotherapy; excitotoxicity; human disease; hypocupremia; insight; macrophage; malformation; meetings; member; mouse model; neonate; novel; null mutation; skeletal; trafficking

DESCRIPTION (provided by applicant): The long-term goals of this proposal are to elucidate the mechanisms by which the nutrient copper is made available for neonatal growth and development. Genetic mutations that disturb copper balance in children can give rise to disease. The most severe of these is Menkes disease, a lethal pediatric disorder that is caused by mutations in the ATP7A copper transporter. Other diseases attributable to mutations in ATP7A include occipital horn syndrome and peripheral motor neuron disease. Moreover, copper and/or the ATP7A protein is implicated in pathogenic processes underlying certain diseases of significant concern, including Alzheimer's disease, cancer chemotherapy resistance, and cardiovascular diseases. Thus, it is clear that understanding the role of ATP7A in specific tissue types is of high significance, not only in areas of copper physiology, but also disease pathogenesis. Progress in understanding the function of ATP7A in specific tissue types has been hampered in large part because null mutations in ATP7A are embryonic lethal in mice. To overcome these obstacles, we have developed a floxed ATP7A mouse model in which ATP7A can be deleted in specific tissues. In the preliminary studies, we demonstrate using an intestinal epithelial cell-specific knockout, that ATP7A is essential for transporting dietary copper into the blood stream to meet the copper demands of neonatal growth. We are now uniquely positioned to answer several long-standing questions in the field. In Specific Aim 1, we will test whether ATP7A-mediated copper transport in the intestine is essential to meet the maternal demands during gestation and lactation. In Specific Aim 2, we will test the novel hypothesis that ATP7A functions in the export of copper from hepatocytes to supply copper to the peripheral organs in the neonatal period, particularly if copper intake via milk is limiting. In Specific Aim 3, we will test the hypothesis that ATP7A in mammary epithelial cells is required for loading of copper into milk to meet the high demand for copper in suckling mice. By identifying the organ-specific pathways by which ATP7A supplies copper for neonatal growth and development, the results of our proposal are certain to have a sustained and powerful impact on the field.

描述（由申请人提供）：该提案的长期目标是阐明营养铜可用于新生儿生长和发育的机制。干扰儿童铜平衡的基因突变会引起疾病。其中最严重的是Menkes疾病，这是一种致命的小儿疾病，是由ATP7A铜转运蛋白突变引起的。归因于ATP7A突变的其他疾病包括枕角综合征和周围运动神经元疾病。此外，铜和/或ATP7A蛋白与某些重大关注的疾病的基础致病过程有关，包括阿尔茨海默氏病，癌症化学疗法耐药性和心血管疾病。因此，很明显，了解ATP7A在特定组织类型中的作用不仅在铜生理学区域，而且在疾病发病机理中具有很高的意义。理解特定组织类型中ATP7A功能的功能的进展在很大程度上受到了阻碍，因为ATP7A中的无效突变是小鼠的胚胎致命。为了克服这些障碍，我们开发了一种flox的ATP7A小鼠模型，其中可以在特定组织中删除ATP7A。在初步研究中，我们证明了使用肠上皮细胞特异性敲除，ATP7A对于将饮食铜运输到血液中以满足新生儿生长的铜需求至关重要。现在，我们有独特的位置可以回答该领域的几个长期问题。在特定目标1中，我们将测试肠中ATP7A介导的铜转运对于满足妊娠和哺乳期间的孕产妇需求至关重要。在特定的目标2中，我们将测试一个新的假设，即ATP7A在新生儿时期向外围器官提供向外围器官提供铜的铜中的功能，尤其是如果通过牛奶摄入铜的摄入量有限。在特定的目标3中，我们将测试以下假设：将铜加载到牛奶中以满足哺乳小鼠中对铜的高需求需要乳腺上皮细胞中的ATP7A。通过确定ATP7A为新生儿生长和发育提供铜的器官特异性途径，我们的提案结果肯定会对该领域产生持续和强大的影响。