Tissue-specific pathways of copper homeostasis in growth and development

描述（由申请人提供）：本提案的长期目标是阐明营养素铜可用于新生儿生长发育的机制。扰乱儿童体内铜平衡的基因突变会引发疾病。其中最严重的是门克斯病，这是一种致命的儿科疾病，由ATP7A铜转运体突变引起。其他可归因于ATP7A突变的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蛋白与某些重要疾病的致病过程有关，包括阿尔茨海默病、癌症化疗耐药性和心血管疾病。因此，了解ATP7A在特定组织类型中的作用，不仅在铜生理学领域，而且在疾病发病机制方面都具有重要意义。了解ATP7A在特定组织类型中的功能的进展在很大程度上受到阻碍，因为ATP7A的零突变在小鼠中是胚胎致死的。为了克服这些障碍，我们开发了一种固定的ATP7A小鼠模型，其中ATP7A可以在特定组织中被删除。在初步研究中，我们通过肠上皮细胞特异性敲除证明，ATP7A对于将膳食铜运输到血液中以满足新生儿生长对铜的需求至关重要。我们现在处于独特的位置，可以回答该领域几个长期存在的问题。在Specific Aim 1中，我们将测试atp7a介导的铜在肠道中的转运是否对满足母体妊娠和哺乳期的需求至关重要。在具体目标2中，我们将验证ATP7A在新生儿期肝细胞铜输出中发挥作用，以向外周器官供应铜，特别是在通过牛奶摄入铜有限的情况下。在Specific Aim 3中，我们将验证乳腺上皮细胞中的ATP7A是将铜装载到乳中以满足哺乳小鼠对铜的高需求所必需的假设。通过确定ATP7A为新生儿生长发育提供铜的器官特异性途径，我们的研究结果肯定会对该领域产生持续而有力的影响。

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.