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.

项目概要/摘要 铜和铁等金属是生物学中必需的金属，因为它们的氧化还原活性有利于基本的细胞 从抗氧化防御到呼吸的过程，以及细胞信号传导中新兴的调节作用。 然而，当体内平衡被破坏时，这种氧化还原活性可能会受到影响，从而导致氧化应激 以及与神经退行性疾病、代谢紊乱和癌症等疾病相关的损害。 金属在生物环境中所处的环境会显着影响其活性和功能。 近年来，监测金属离子的工具不断增多，并阐明了金属离子的多样性。 生物学中的形态形成，但其中许多工具都专注于探测细胞内空间中的金属。 评估细胞外液（例如血浆）中金属状态的最先进方法要么侧重于绝对值 虽然这些方法提供了定量或评估有限数量的含金属物质的能力。 对于金属缺乏或过载的极端情况有重要的洞察力，微妙的不平衡更具挑战性 使用现有方法进行诊断和理解。该研究计划的目标是扩展和理解。 阐明细胞外空间的金属形态，特别是血浆和间质中的金属形态 在绘制血浆中的金属图谱时，我们的策略重点是确定生物无机化学。 称为激素的动态生物分子群是化学信使。 身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 在我们称之为“金属内分泌学”的领域中，保持对内部和外部刺激的平衡。 我们寻求识别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 此外，我们还寻求启动新陈代谢、能量消耗、日常生物节律和营养健康。 对间隙空间相对未经探索的无机生物化学的研究，其中包含 这种环境给离体分析的收集和分离带来了挑战。 寻求开发针对该细胞外区域的成像剂，对感兴趣的特定金属离子做出反应。 使用受化学生物学、生物医学工程和光谱学启发的方法，我们建议 生物发光和基于肽的成像平台，与基于化学选择性反应的偶联 该提案中产生的见解和技术将直接用于探测间隙金属。 影响营养治疗、激素治疗开发和金属状态生物标志物发现。