Molecular Tools to Illuminate Copper Transport and Homeostasis

摘要 铜是一种对人体健康至关重要的必需微量营养素。作为金属蛋白中的一个重要辅因子， 需要支持许多基本的生物功能，包括呼吸，超氧化物解毒， 胺的降解以及铁的动员和吸收。细胞铜含量受到严格控制 通过膜转运蛋白、伴侣蛋白、配体和转录因子的复杂网络。如果 在错误的环境中，铜有能力催化羟基自由基的产生， 其他活性氧，一种常见的有害机制，在神经系统中有深远的影响， 退行性疾病（ALS和阿尔茨海默病）和与铜误分泌相关的疾病 （Menkes和Wilson病）。由于病理条件往往是由毒性引起的错误定位 铜，而不是未能提供铜的铜酶，详细了解铜的相互作用 在细胞蛋白质组中是至关重要的。这项拨款申请的目的是发展 分子工具，将使研究人员能够解剖和发现新的铜贩运途径，无论是在 正常生理状态及其在与铜稳态异常相关疾病中的改变。中 在更广泛的背景下，预计拟议的工具对长期发展至关重要， 新的诊断和治疗方法，以对抗铜相关的人类疾病。

Abstract Copper is an essential trace nutrient critical to human health. As a prominent cofactor in metalloproteins, it is required to support many fundamental biological functions, including respiration, superoxide detoxification, degradation of amines, and the mobilization and uptake of iron. Cellular copper levels are tightly controlled through a complex network of membrane transporters, chaperone proteins, ligands, and transcription factors. If placed in the wrong environment, copper has the ability to catalyze the production of hydroxyl radicals and other reactive oxygen species, a common deleterious mechanism that has profound implications in neuro- degenerative diseases (ALS and Alzheimer’s disease) and diseases associated with copper mistrafficking (Menkes and Wilson’s disease). As the pathological conditions are often caused by the toxicity of mislocalized copper rather than the failure to deliver copper to cuproenzymes, detailed knowledge of the copper interactions within the cellular proteome is of fundamental importance. The goal of this grant application is to develop molecular tools that will allow researchers to dissect and discover new copper trafficking pathways, both under normal physiological conditions and their alterations in diseases associated with copper dyshomeostasis. In a broader context, the proposed tools are expected to be of critical importance for the long-term development of novel diagnostic and therapeutic methods to combat copper related human diseases.