CALMODULIN, AGING, AND CALCIUM HOMEOSTASIS

钙调蛋白、衰老和钙稳态

• 批准号: 8170721
• 负责人: THOMAS Comey SQUIER
• 金额: $ 3.21万
• 依托单位: BATTELLE PACIFIC NORTHWEST LABORATORIES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170721
• 关键词: Affect; Aging; Autocrine Communication; Calcium; Calmodulin; Cell physiology; Cells; Cellular Stress; Chronic; Computer Retrieval of Information on Scientific Projects Database; Enzymes; Funding; Goals; Grant; Homeostasis; Immune response; Inflammation; Inflammatory; Inflammatory Response; Institution; Interferons; Kinetics; Macrophage Activation; Mediating; Modification; Molecular; Oxidative Stress; Pathway interactions; Proteins; Regulation; Research; Research Personnel; Resources; Respiratory Burst; Role; Site; Source; Tissues; United States National Institutes of Health; age related; cytokine; design; healthy aging; killings; macrophage; nitration; oxidation; repaired; response; sensor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our long-term goal is to identify the molecular mechanisms that result in age-dependent declines in cell function and increased sensitivity to cellular stress and chronic inflammatory responses. We hypothesize that the site-specific oxidation and nitration of critical protein sensors of oxidative stress, such as calmodulin (CaM), modulate cellular responses to chronic inflammation common to aging tissues. The focus of this proposal is to understand a) the normal cellular mechanisms that maintain cellular homeostasis through the efficient repair and degradation of oxidized proteins, and b) how observed age-dependent oxidative modifications to CaM affect cell function. Our focus is to determine the role of CaM and its oxidation on macrophage function, because age-dependent declines in macrophage function contribute to diminished immune responses and the accumulation of nonfunctional cells whose clearance is necessary for healthy aging. Further, we have recently identified a previously unrecognized critical role for CaM in mediating macrophage activation and bacterial killing that involves the coordinate regulation of the oxidative burst through iNOS activation and autocrine signaling involving TNF¿-dependent pathways. We expect that age-dependent decreases in CaM abundance and associated age-dependent increases in the oxidized CaM fraction contribute to observed decreases in macrophage function. We suggest that age-dependent increases in the abundances of the circulating cytokines TNF¿ and IFN- ¿ associated with macrophage priming induce a chronic oxidative stress that contributes to age-dependent declines in macrophage function through CaM oxidation. We have designed two specific aims: In Aim 1, levels of chronic inflammation and abundances of repair proteins will be modulated in RAW macrophages. 1: Determine how inflammatory cytokines affect the kinetics of CaM oxidation, repair, and degradation in relationship to cell function. 2: Understand how site-specific oxidation differentially regulates CaM-dependent enzymes.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 对于中心来说，它不一定是研究者的机构。 我们的长期目标是确定导致细胞功能随年龄下降以及对细胞应激和慢性炎症反应敏感性增加的分子机制，我们发现氧化应激的关键蛋白质传感器的位点特异性氧化和硝化，例如钙调蛋白 (CaM)，调节细胞对衰老组织常见的慢性炎症的反应，该提案的重点是了解 a) 通过氧化蛋白质的有效修复和降解维持细胞稳态的正常细胞机制， b) 观察到的 CaM 年龄依赖性氧化修饰如何影响细胞功能 我们的重点是确定 CaM 及其氧化对巨噬细胞功能的作用，因为年龄依赖性巨噬细胞功能下降会导致免疫反应减弱和非功能性物质的积累。此外，我们最近发现了 CaM 在介导巨噬细胞活化和细菌杀伤方面的一个先前未被认识的关键作用，其中涉及通过 iNOS 协调调节氧化爆发。涉及 TNF 的激活和自分泌信号传导我们预计，CaM 丰度的年龄依赖性减少和氧化 CaM 部分的年龄依赖性增加有助于观察到的巨噬细胞功能的减少，我们认为循环细胞因子 TNF 丰度的年龄依赖性增加。和 IFN- ¿与巨噬细胞启动相关的慢性氧化应激会通过 CaM 氧化导致巨噬细胞功能的年龄依赖性下降：在目标 1 中，原始巨噬细胞中的慢性炎症水平和修复蛋白丰度将受到调节。 1：确定炎症细胞因子如何影响与细胞功能相关的 CaM 氧化、修复和降解动力学。 2：了解位点特异性氧化如何差异调节 CaM 依赖性酶。