INHERITED DISORDERS OF COPPER TRANSPORT

拟议研究的总体目标是了解必需微量元素铜是如何在哺乳动物细胞和组织中运输、储存和传递到其靶蛋白的。我们将研究铜被吸收的机制，传递到分泌途径，并通过膜运输到其他蛋白质中，或通过Menkes （MNK）和Wilson （WND）病基因产物输出。这些研究将进一步阐明铜在疾病表型发病机制中的作用。具体目的如下：1)验证我们的假设，即CTR1是哺乳动物必需的高亲和力铜摄取蛋白。2)了解铜伴侣蛋白HAH1如何将铜传递给MNK atp酶。3)描述通过位点定向诱变进行铜转运所需的MNK atp酶的特征。4)验证我们的假设，即MNK和WND atp酶介导不同和相互作用的功能。

The overall goal of the proposed research is to understand how the essential trace element copper is transported, stored, and delivered to its target proteins in mammalian cells and tissues. We shall examine the mechanisms by which copper is taken up, relayed to the secretory pathway, and transported across a membrane for incorporation into other proteins or for export by the Menkes (MNK) and Wilson (WND) disease gene products. These studies will further elucidate the roles for copper in the pathogenesis of disease phenotypes. The specific aims are the following: l) To test our hypothesis that CTR1 is an essential high-affinity copper uptake protein in mammals. 2) To understand how the copper chaperone protein HAH1 relays copper to the MNK ATPase. 3) To delineate the features of the MNK ATPase that are required for copper transport by site-directed mutagenesis. 4) To test our hypothesis that the MNK and WND ATPases mediate different and reciprocal functions.