Molecular Imaging Probes to Study Metal Biology

 说明(申请人提供)：铜是一种基本的金属营养素，在人类健康、衰老和疾病中扮演着重要的角色。铜的强氧化还原活性是从呼吸到抗氧化防御再到伤口愈合等一系列不同的生理过程所必需的。然而，与此同时，铜稳态的不受调控的失衡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。我们正在开发和应用新的化学工具，用于生命系统中铜的分子成像，长期目标是了解这种金属如何以及在什么背景下对正常生理以及衰老和疾病做出贡献。这一竞争性更新应用将集中在阐明铜在脂解中的作用，脂解是脂代谢的中心过程，对维持身体的能量储存至关重要，但也有助于 代谢性疾病，如肥胖和糖尿病。具体目标包括：开发具有增强的光稳定性的新型荧光铜传感器来监测铜的动态变化和更广泛的结合亲和力以访问更广泛的细胞铜库，应用这些新的化学工具来探索铜信号在脂肪细胞模型中对脂肪分解的贡献，以及对新发现的介导脂解信号通路的铜-蛋白质靶标进行生化表征。

 DESCRIPTION (provided by applicant): Copper is an essential metal nutrient that plays important roles in human health, aging, and disease. The potent redox activity of copper is required for a diverse array of physiological processes ranging from respiration to antioxidant defense to wound healing. At the same time, however, unregulated imbalances in 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. We are developing and applying new chemical tools for molecular imaging of copper in living systems with the long-term goal of understanding how and in what context this metal contributes to normal physiology as well as aging and disease. This competitive renewal application will focus on elucidating the roles of copper in lipolysis, a central process i lipid metabolism that is essential for maintaining the body's energy stores but also contributes to metabolic diseases such as obesity and diabetes. Specific aims include: developing new fluorescent copper sensors with enhanced photostability to monitor of copper dynamics and a broader range of binding affinities to access a broader range of copper pools in cells, applying these new chemical tools to probe the contributions of copper signaling to lipolysis in adipocyte cell models, and biochemical characterization of newly identified copper-protein targets that mediate lipolytic signaling pathways.