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: 10661576
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661576
• 关键词: Affect; Antioxidants; Area; Bathing; Biochemistry; Bioinorganic Chemistry; Biological; Biological Rhythm; Biology; Biomedical Engineering; Cardiovascular Diseases; Cell physiology; Cells; Chemicals; Collection; Communication; Copper; Coupled; Diabetes Mellitus; Diagnosis; Disease; Emerging Technologies; Endocrine system; Energy consumption; Environment; Equilibrium; Extracellular Fluid; Extracellular Space; Gland; Health; Homeostasis; Hormones; Intracellular Space; Investigation; Ions; Iron; Liquid substance; Liver diseases; Locales; Malignant Neoplasms; Maps; Metabolic Diseases; Metabolism; Metals; Methods; Monitor; Nerve Degeneration; Nutritional; Organ; Oxidation-Reduction; Oxidative Stress; Peptides; Plasma; Population Dynamics; Reaction; Research; Respiration; Role; Signal Transduction; Spectrum Analysis; Stimulus; Tissues; 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学中必不可少的金属，因为它们的氧化还原活性促进了基本的细胞 从抗氧化剂防御到呼吸以及新兴的调节作用在细胞信号传导中的过程。 但是，可以在破坏其稳态时确定这种氧化还原活性，从而导致氧化应激 以及与神经变性，代谢性疾病和癌症有关的疾病。 生物环境中金属住宅的背景会显着影响其活性和功能。 近年来，监测金属离子的工具有所增加，并照亮了金属的多样性 生物学的规范，但其中许多工具集中在细胞内空间中的金属上。国家 - 用于评估细胞外液中金属状态（例如血浆）中金属状态的ART方法的重点是绝对 定量或评估有限数量的含金属的物种。虽然提供了这些方法 对金属缺乏或超负荷极端情况的重要洞察力，微妙的失衡是更挑战的 使用可用方法诊断和理解。该研究计划的目的是扩展和 阐明细胞外空间的金属规范，特别是在血浆和间隙中 空间。在映射血浆中的金属时，我们的策略着重于确定生物无机化学 被称为激素的生物分子的动态种群。激素是化学信使 人体内分泌系统的信息从专门的腺体到目标时间和器官到 响应内部和外部刺激以保持平衡。在我们称为“金属内分泌学”的领域中， 我们试图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 功能或训练如何调节金属的水平，并评估这些相互作用如何影响 代谢，能源消耗，每日生物节奏和营养健康。此外，我们试图发起 对间质空间中相对无机生物化学的相对无机生物化学的研究，其中包含 贝型器官的液体。这个环境在离体分析方面提出了挑战和隔离，我们因此 寻求开发针对这种细胞外部位置的成像剂，该剂对特定的金属离子有反应。 使用受化学生物学，生物医学工程和光谱法启发的方法，我们提出 与化学选择性反应耦合的生物发光和基于胡椒的成像平台 探测间质金属的策略。该提案中产生的见解和技术将直接 影响营养疗法，马内治疗发展和生物标志物发现金属状态。