Chemical Probes to Study Metal Biology

项目摘要/摘要 铜是一种必需的金属营养素，在人类健康和疾病中发挥着重要作用。强大的氧化还原能力 铜的活性是各种生理过程所必需的，包括呼吸作用、抗氧化剂 防御、神经递质合成和伤口愈合。然而，铜稳态失调可能会 导致代谢性疾病，如肥胖和糖尿病，以及癌症、心脏病和 神经退行性疾病，通常是通过异常的氧化应激和损伤途径。帮助破译 铜对健康和疾病状态的贡献，我们正在开发新的化学工具来实现 从亚细胞到多种生物模型的生命系统中铜的特异性成像 从隔室到细胞再到整个动物。科学前提是，构建一个铜成像工具包将 提供基础化学试剂以加深我们对铜在生理学和生理学上的作用的理解 以及病态的情况。这一极具竞争力的续订应用由设计创新推动，我们 发明新的可推广的、基于活动的铜检测传感平台，以及在 合成和使用多种表征技术，将这些工具应用于细胞和动物模型。 具体地说，我们将研究蛋白质标记的铜探针，以研究铜是如何存储、交易和利用的 在亚细胞水平上，化学发光指示器能够实现动态和纵向铜成像 活体动物水平，并研究探讨铜如何有助于管理神经元中的氧化应激 在斑马鱼模型中培养和调节神经回路和行为。

Project Summary/Abstract Copper is an essential metal nutrient that plays important roles in human health and disease. The potent redox activity of copper is required for a diverse array of physiological processes including respiration, antioxidant defense, neurotransmitter synthesis, and wound healing. However, dysregulated copper homeostasis can contribute to metabolic diseases like obesity and diabetes as well as cancer, heart disease, and neurodegenerative disorders, often through aberrant oxidative stress and damage pathways. To help decipher the contributions of copper to healthy and disease states, we are developing new chemical tools to enable copper-specific imaging in living systems across a broad range of biological models, from subcellular compartments to cells to whole animals. The scientific premise is that building a copper imaging toolkit will provide foundational chemical reagents to further our understanding of the roles of copper in both physiological and pathological situations. This competitive renewal application is driven by design innovations where we invent new generalizable, activity-based sensing platforms for copper detection, as well as scientific rigor in the synthesis and use of multiple characterization techniques to apply these tools in cell and animal models. Specifically, we will pursue protein-labeled copper probes to study how copper is stored, trafficked, and utilized at the subcellular level, chemiluminescent indicators to enable dynamic and longitudinal copper imaging at the live animal level, and studies to probe how copper contributes to managing oxidative stress in neuronal cultures and regulating neural circuitry and behavior in zebrafish models.