Chemical Probes to Study Metal Biology

项目概要/摘要 铜是一种必需的金属营养素，在人类健康和疾病中起着重要作用。有效的氧化还原 铜的活性是多种生理过程所必需的，包括呼吸、抗氧化、 防御、神经递质合成和伤口愈合。然而，铜稳态失调， 导致肥胖和糖尿病等代谢疾病，以及癌症，心脏病， 神经退行性疾病，通常通过异常的氧化应激和损伤途径。来帮助破译 铜对健康和疾病状态的贡献，我们正在开发新的化学工具， 铜特异性成像在生活系统中的广泛的生物模型，从亚细胞 隔室到细胞再到整个动物。科学的前提是，建立一个铜成像工具包， 提供基础化学试剂，以进一步了解铜在生理和病理中的作用。 和病态的情况。这一极具竞争力的更新应用是由设计创新驱动的， 发明新的可推广的，基于活动的铜检测传感平台，以及科学严谨的 综合和使用多种表征技术，将这些工具应用于细胞和动物模型。 具体来说，我们将追求蛋白质标记的铜探针，研究铜是如何储存，贩运和利用 在亚细胞水平，荧光指示剂，使动态和纵向铜成像在 活体动物水平，以及探索铜如何有助于管理神经元中的氧化应激的研究。 文化和调节神经回路和行为的斑马鱼模型。

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.