Molecular Imaging Probes to Study Redox Biology

描述（由申请人提供）：活性氧（ROS）是一类在人类健康、衰老和疾病中发挥重要作用的小分子。ROS的产生和消耗的不平衡导致氧化应激和蛋白质、脂质和核酸的损伤，这反过来又会导致组织和器官的功能随着时间的推移而下降，并导致从癌症到心血管疾病到神经退行性疾病的重大疾病。与此同时，新出现的数据表明，一种特殊的ROS，过氧化氢（H2O2），也可以产生生理信号的目的，介导的过程，从伤口愈合到神经传递，通过调节细胞生长，分化和迁移途径的方式类似于典型的小分子信号一氧化氮（NO）。我们正在开发和应用新的化学工具，用于H2O2的分子成像，长期目标是了解这种氧代谢物如何以及在何种情况下有助于正常生理，衰老和疾病。本次竞争性更新申请的具体目标包括开发新的探针，允许以亚细胞分辨率对H2O2进行化学选择性成像，创造新的成像剂，可用于通过近红外荧光或生物发光模式监测活生物体中的H2O2通量，并应用这些和相关的化学工具来阐明H2O2产生对神经干细胞中信号传导和应激途径的贡献和神经元。

DESCRIPTION (provided by applicant): Reactive oxygen species (ROS) are a class of small molecules that play important roles in human health, aging, and disease. Imbalances in the production and consumption of ROS cause oxidative stress and damage of proteins, lipids, and nucleic acids, which can in turn lead to functional decline of tissues and organs over time and contribute to major diseases ranging from cancer to cardiovascular disorders to neurodegenerative diseases. At the same time, emerging data shows that one particular ROS, hydrogen peroxide (H2O2), can also be produced for physiological signaling purposes to mediate processes, from wound healing to neurotransmission, by regulating cell growth, differentiation, and migration pathways in a manner akin to the canonical small-molecule signal nitric oxide (NO). We are developing and applying new chemical tools for molecular imaging of H2O2 with the long-term goal of understanding how and in what context this oxygen metabolite contributes to normal physiology, aging, and disease. Specific aims for this competitive renewal submission include developing new probes that will allow chemoselective imaging of H2O2 with subcellular resolution, creating new imaging agents that can be used to monitor H2O2 fluxes in living organisms by near-IR fluorescence or bioluminescence modalities, and applying these and related chemical tools for elucidating the contributions of H2O2 production to signaling and stress pathways in neural stem cells and neurons.