Chemical Probes to Study Copper Biology

项目总结/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、激素和神经递质的生物合成和代谢。然而，铜的失调 体内平衡可导致癌症、代谢疾病如肥胖症和糖尿病，以及心脏病和 神经退行性疾病，通常通过异常的氧化应激和损伤途径。我们 开发新的化学试剂，使生物模型中的铜特异性成像， 铜对健康和疾病状态的贡献，跨越亚细胞到细胞到动物水平， 沿着化学蛋白质组学方法来识别和靶向铜依赖性疾病的脆弱性。的 科学前提是，建立铜成像和蛋白质组学工具包将提供基础化学 试剂，以进一步我们的铜在生理和病理学中的作用的理解，并打开新的 治疗干预的途径。这一极具竞争力的更新应用是由设计创新驱动的 在那里，我们发明了新的可推广的，基于活动的传感平台，用于铜检测和基于活动的 蛋白质组学的铜依赖性疾病的目标，以及科学严谨的合成和使用多种 表征技术，将这些工具应用于细胞和动物模型。具体来说，我们将研究蛋白质- 标记的铜探针，研究铜是如何储存，贩运，并利用在亚细胞和细胞 水平，荧光指示器，以实现组织和动物的动态和纵向铜成像 水平和化学蛋白质组学方法来鉴定铜依赖性可药用位点和共价片段 铅化合物对这些目标。

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, and hormone and neurotransmitter biosynthesis and metabolism. However, dysregulated copper homeostasis can contribute to cancer, metabolic diseases like obesity and diabetes, and heart and neurodegenerative disorders, often through aberrant oxidative stress and damage pathways. We are developing new chemical reagents that enable copper-specific imaging in biological models to help decipher the contributions of copper to healthy and disease states, spanning the subcellular to cellular to animal level, along with chemoproteomics approaches to identify and target copper-dependent disease vulnerabilities. The scientific premise is that building a copper imaging and proteomics toolkit will provide foundational chemical reagents to both further our understanding of the roles of copper in physiology and pathology and open new avenues for therapeutic intervention. This competitive renewal application is driven by design innovations where we invent new generalizable, activity-based sensing platforms for copper detection and activity-based proteomics for copper-dependent disease targets, 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 and cellular level, chemiluminescent indicators to enable dynamic and longitudinal copper imaging at the tissue and animal level, and chemoproteomics approaches to identify copper-dependent druggable sites and covalent fragment lead compounds against these targets.