Metalloendocrinology: Mapping Bioinorganic Chemistry in the Extracellular Space

金属内分泌学：绘制细胞外空间的生物无机化学图谱

• 批准号: 10192761
• 负责人: Marie C. Heffern
• 金额: $ 36.19万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192761
• 关键词: Affect; Antioxidants; Area; Biochemistry; Bioinorganic Chemistry; Biological; Biological Rhythm; Biology; Biomedical Engineering; Cardiovascular Diseases; Cell physiology; Cells; Chemicals; Collection; Communication; Consumption; Copper; Coupled; Diabetes Mellitus; Diagnosis; Disease; Emerging Technologies; Endocrine system; Environment; Equilibrium; Extracellular Fluid; Extracellular Space; Gland; Health; Homeostasis; Hormones; Intracellular Space; Investigation; Ions; Iron; Liquid substance; Liver diseases; Locales; Malignant Neoplasms; Metabolic Diseases; Metabolism; Metals; Methods; Monitor; Nerve Degeneration; Nutritional; Organ; Oxidation-Reduction; Oxidative Stress; Peptides; Plasma; Population; Reaction; Research; Respiration; Role; Signal Transduction; Spectrum Analysis; Stimulus; Tissues; base; biomarker discovery; extracellular; hormone therapy; imaging agent; imaging platform; insight; interest; interstitial; novel therapeutics; oxidative damage; programs; response; targeted agent; therapy development; tool

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.

项目摘要/摘要 铜和铁等金属是生物中必不可少的金属，因为它们的氧化还原活性促进了基本细胞的生长。 从抗氧化防御到呼吸作用，以及在细胞信号传递中新出现的调节作用。 然而，当它们的动态平衡被破坏时，这种氧化还原活性可能是有害的，导致氧化应激。 以及与神经退行性变、代谢紊乱和癌症等疾病相关的损害。这个 金属在生物环境中所处的环境对其活性和功能有很大影响。 近年来，用于监测金属离子的工具有所增加，并阐明了金属的多样性 生物学中的物种形成，但这些工具中的许多都专注于探测细胞内空间的金属。国家-- 用于评估细胞外液(如血浆)中金属状态的最先进方法 对有限数量的含金属物种进行量化或评估。虽然这些方法提供了 对金属短缺或过载的极端情况的重要洞察，微妙的失衡更具挑战性 用可用的方法进行诊断和理解。这项研究计划的目标是扩大和 阐明细胞外间隙的金属形态，特别是在血浆和间质中。 太空。在绘制血浆中金属的图谱时，我们的策略侧重于确定生物无机化学。 一种称为荷尔蒙的生物分子的动态种群。荷尔蒙是化学信使 人体内分泌系统的一部分，它将信息从专门的腺体输送到目标组织和器官 对内部和外部的刺激保持平衡。在我们称之为“金属内分泌学”的领域， 我们试图确定与血浆中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 新陈代谢、能量消耗、日常生物节律和营养健康。此外，我们寻求发起 研究相对未被探索的组织间隙的无机生物化学，其中包含 沐浴器官的液体。这种环境对体外分析的收集和分离提出了挑战，因此 寻求开发针对这种细胞外场所的显像剂，以对感兴趣的特定金属离子做出反应。 利用化学生物学、生物医学工程和光谱学的启发，我们提出了这两种方法 与化学选择性反应相偶联的生物发光和基于多肽的成像平台 探测间隙金属的策略。从该提案中产生的见解和技术将直接 影响营养治疗、激素治疗的发展，以及金属状态的生物标志物发现。