Metalloendocrinology: Mapping Bioinorganic Chemistry in the Extracellular Space

项目总结/摘要 金属如铜和铁是生物体中的必需金属，因为它们的氧化还原活性促进基本的细胞增殖， 从抗氧化防御到呼吸的过程，沿着细胞信号传导中新兴的调节作用。 然而，当它们的体内平衡被破坏时，这种氧化还原活性可能是有害的，导致氧化应激 以及与跨越神经变性、代谢紊乱和癌症的疾病相关的损伤。的 金属存在于生物环境中的环境显著影响其活性和功能。 近年来，用于监测金属离子的工具有所增加，并阐明了金属离子的多样性。 生物学中的物种形成，但这些工具中的许多都集中在探测细胞内空间中的金属。国家- 用于评估细胞外液如血浆中金属状态的现有技术方法集中于绝对 定量或评估有限数量的含金属物质。虽然这些方法提供了 对于金属缺乏或过载的极端情况，微妙的不平衡更具挑战性， 用现有的方法进行诊断和理解。这项研究计划的目的是扩大和 阐明细胞外空间的金属形态，特别是在血浆和间质中 空间在绘制血浆中的金属时，我们的策略集中在确定生物无机化学 一种动态的生物分子群，称为激素。激素是化学信使 它是人体内分泌系统的一部分，将信息从专门的腺体传递到目标组织和器官， 保持平衡以应对内部和外部刺激。在我们称之为"金属内分泌学"的领域， 我们试图找出与血浆中的金属相互作用的激素，确定金属如何影响激素， 功能或激素如何调节金属水平，并评估这些相互作用如何影响 代谢、能量消耗、日常生物节律和营养健康。此外，我们还寻求发起 研究相对未探索的间隙空间的无机生物化学，其中包含 冲洗器官的液体。这种环境为离体分析的收集和分离提供了挑战，因此， 寻求开发靶向该细胞外区域的成像剂，其响应于感兴趣的特定金属离子。 我们采用受化学生物学、生物医学工程和光谱学启发的方法，提出了这两种方法 生物发光和基于肽的成像平台，其与基于化学选择性反应的 探测间隙金属的策略。从这一提议中产生的见解和技术将直接 影响营养治疗、激素治疗开发和金属状态生物标志物发现。

Project Summary/Abstract Metals such as copper and iron are essential metals in biology, as their redox activities facilitate basic cellular processes ranging from antioxidant defense to respiration, along with emerging regulatory roles in cell signaling. However, this redox activity can be detrimental when their homeostasis is disrupted, leading to oxidative stress and damage associated with diseases spanning neurodegeneration, metabolic disorders, and cancer. The context in which a metal resides within a biological environment significantly influences its activity and function. Recent years have seen a rise in tools for monitoring metal ions and have illuminated the diversity in metal speciation in biology, but many of these tools are focused on probing metals in the intracellular space. The state- of-the-art methods for assessing metal status in extracellular fluids such as blood plasma focus either on absolute quantitation or evaluate a limited number of metal-containing species. While these methods have offered important insight into extreme cases of metal deficiency or overload, subtle imbalances are more challenging to diagnose and understand with the available methods. The objective of this research program is to expand and elucidate the metal speciation of the extracellular space, specifically in the blood plasma and the interstitial space. In mapping the metals in blood plasma, our strategy focuses on determining the bioinorganic chemistry of a dynamic population of biological molecules known as hormones. Hormones are the chemical messengers of the body’s endocrine system that carries information from specialized glands to target tissues and organs to maintain balance in response to internal and external stimuli. In an area that we term “metalloendocrinology”, we seek to identify hormones that interact with metals in the plasma, determine how metals influence hormone function or how hormones may regulate the levels of metals, and assess how these interactions impact metabolism, energy consumption, daily biological rhythms, and nutritional health. Additionally, we seek to initiate investigations into the relatively-unexplored inorganic biochemistry of the interstitial space, which contains the fluid that bathes the organs. This milieu offers challenges in collection and isolation for ex vivo analysis, we thus seek to develop imaging agents targeted to this extracellular locale that respond to specific metal ions of interest. Using approaches inspired by chemical biology, biomedical engineering, and spectroscopy, we propose both bioluminescent and peptide-based imaging platforms that are coupled to chemoselective reaction-based strategies for probing interstitial metals. The insights and technologies that emerge from this proposal will directly impact nutritional treatments, hormone therapy development, and biomarker discovery for metal status.