Molecular Tools to Illuminate Copper Transport and Homeostasis

 描述（由申请人提供）：铜是一种对人体健康至关重要的必需微量营养素。作为金属蛋白中一个重要的辅因子，它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，铁的动员和吸收。细胞铜水平通过膜转运蛋白、伴侣蛋白、配体和转录因子的复杂网络被严格控制。如果放置在错误的环境中，铜能够催化羟基自由基和其他活性氧物质的产生，这是一种常见的有害机制，对神经退行性疾病（ALS和阿尔茨海默病）和与铜误释放相关的疾病（门克斯和威尔逊病）具有深远的影响。由于病理条件往往是由错误定位的铜的毒性，而不是未能提供铜的铜酶，细胞蛋白质组内的铜相互作用的详细知识是至关重要的。这项拨款申请的目的是 开发分子工具，使研究人员能够解剖和发现新的铜运输途径，无论是在正常的生理条件下，还是在与铜代谢障碍相关的疾病中。在更广泛的背景下，预计所提出的工具对于长期开发新的诊断和治疗方法以对抗铜相关的人类疾病至关重要。

 DESCRIPTION (provided by applicant): 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, a 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 wider 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.