Molecular Tools to Illuminate Copper Transport and Homeostasis

摘要 铜是人体必需的微量营养素，对人体健康至关重要。作为金属蛋白中一种重要的辅因子，它是 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。细胞铜水平受到严格控制 通过膜转运蛋白、伴侣蛋白、配体和转录因子组成的复杂网络。如果 放置在错误的环境中，铜具有催化产生羟基自由基和 其他活性氧物种，这是一种常见的有害机制，对神经- 退化性疾病(肌萎缩侧索硬化症和阿尔茨海默病)以及与铜作弊相关的疾病 (孟克斯和威尔逊病)。由于病理情况往往是由于毒性定位不当所致。 铜，而不是铜向铜酶传递失败，详细了解铜的相互作用 在细胞蛋白质组中是至关重要的。这项赠款申请的目标是开发 分子工具，使研究人员能够解剖和发现新的铜运输途径，这两种途径都是在 铜代谢紊乱相关疾病的正常生理状态及其变化。在一个 在更广泛的背景下，预计拟议的工具将对以下方面的长期发展至关重要 抗击与铜有关的人类疾病的新诊断和治疗方法。

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.