Supplement: Metalloendocrinology: Mapping Bioinorganic Chemistry in the Extracellular Space

补充：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: 10689412
• 负责人: Marie C. Heffern
• 金额: $ 6.09万
• 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/10689412
• 关键词: Address; Affect; Antioxidants; Area; Behavior; Binding; Biochemistry; Bioinorganic Chemistry; Biological; Biological Assay; Biological Markers; Biological Process; Biological Rhythm; Biology; C-Peptide; C-terminal; Cell Line; Cell Surface Receptors; Cell membrane; Cells; Charge; Chemicals; Consensus; Copper; Diabetes Mellitus; Diet; Discipline; Disease; Disparity; Dose; Energy consumption; Environment; Enzymes; Equilibrium; Event; Extracellular Space; Foundations; Future; G-Protein-Coupled Receptors; Goals; Health; HepG2; Hepatocyte; Homeostasis; Hormones; Human; In Vitro; Influentials; Insulin; Investigation; Ions; Iron; Knowledge; Length; Libraries; Link; Liquid substance; Literature; Maps; Mediating; Membrane; Mentors; Metabolism; Metals; Micronutrients; Molecular; Molecular Chaperones; Monitor; Nutritional; Organ; Organism; Orphan; Oxidation-Reduction; Oxidative Stress; Pathology; Pathway interactions; Peptide Receptor; Peptides; Physiology; Plasma; Plasma Proteins; Play; Process; Proinsulin; Protein Analysis; Proteins; Proteomics; Reporting; Research; Research Design; Respiration; Rodent; Role; Signal Transduction; System; Techniques; Technology; Testing; Therapeutic; Tissues; Training; Transition Elements; Vascular Diseases; Work; biomarker development; experimental study; extracellular; hypocupremia; in vivo; inflammatory marker; insight; interest; kidney dysfunction; nanodisk; parent grant; parent project; peptide hormone; prohormone; receptor; receptor binding; screening; trafficking; transcriptome sequencing

PROJECT ABSTRACT Copper is an essential micronutrient in biology, playing fundamental roles in processes such as respiration and antioxidant defense. The context in which a copper ion resides is vital to its activity, and its miscompartmentalization and imbalances is associated with a host of disorders. While technologies have emerged to investigate intracellular copper dynamics, the extracellular copper pool is relatively under- characterized. The parent grant of this supplement seeks to elucidate the speciation of metals in the extracellular space, with a focus on the interplay of metals with another dynamic component in the extracellular environment, hormones. The main research of this objective focuses on a particular peptide with hormone-like functions, C- peptide, a 31-mer derived from the proinsulin protein. Historically undervalued as an innocent secondary marker for insulin, C-peptide is of increasing interest for its bioactivity independent of insulin. However, its advancement has been hampred by lack of mechanistic understanding. Work under the parent project has shown that C- peptide can directly bind to copper, an event that can modulate C-peptide's activity. In Aim 1 of this proposal, we seek to determine whether and how C-peptide and its truncates affect copper trafficking. Preliminary work suggests that the metal-binding interaction can shift the homeostatic balance of the metal. A combination of in vitro and in vivo work will seek to analyze the pathways that drive the interplay between C-peptide and copper. Aim 2 seeks to leverage the interactions of copper and C-peptide to identify a plasma membrane receptor for the peptide. While an orphan GPCR, GPR146, has been proposed as a partner for C-peptide, this claim remains debated. We hypothesize that metal interactions with the peptide, which is rich in negatively-charged residues, may be influential in receptor recognition. This aim will screen for C-peptide interactions with a library of orphan GPCRs in the presence and absence of transition metals to determine whether metals are integral to receptor recognition, and if so, identify a cognate receptor for the peptide. To achieve these research goals, the candidate to be supported by this supplement will be trained across disciplines with a multifaceted mentoring team to bring molecular insight to metalloendocrinological processes.

项目摘要 铜是生物学中必需的微量营养素，在呼吸和呼吸等过程中发挥着重要作用。 抗氧化防御。铜离子所处的环境对其活性至关重要，并且 区室错误和失衡与许多疾病有关。虽然技术已经 为研究细胞内铜动态而出现，细胞外铜池相对不足 特点。本补充品的家长资助旨在阐明细胞外金属的形态 空间，重点关注金属与细胞外环境中另一种动态成分的相互作用， 荷尔蒙。该目标的主要研究集中于具有激素样功能的特定肽，C- 肽，一种源自胰岛素原蛋白的 31 聚体。历史上作为无辜的次要标记被低估 对于胰岛素，C 肽因其独立于胰岛素的生物活性而受到越来越多的关注。然而其进步 由于缺乏机制理解而受到阻碍。父项目下的工作表明，C- 肽可以直接与铜结合，从而调节 C 肽的活性。在本提案的目标 1 中，我们 试图确定 C 肽及其截短物是否以及如何影响铜贩运。前期工作 表明金属结合相互作用可以改变金属的稳态平衡。的组合在 体外和体内工作将寻求分析驱动 C 肽和铜之间相互作用的途径。 目标 2 寻求利用铜和 C 肽的相互作用来识别质膜受体 肽。虽然孤儿 GPCR，GPR146，已被提议作为 C 肽的伙伴，但这种说法仍然存在 争论了。我们假设金属与富含负电荷残基的肽相互作用， 可能对受体识别有影响。该目标将筛选与孤儿文库的 C 肽相互作用 GPCR 在存在和不存在过渡金属的情况下确定金属是否是受体的组成部分 识别，如果是，则识别该肽的同源受体。为了实现这些研究目标，候选人 得到该补充品支持的人将接受多方面指导团队的跨学科培训，以带来 对金属内分泌过程的分子洞察。