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.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 我们的长期目标是确定导致年龄依赖性细胞功能下降的分子机制，并提高对细胞应激和慢性炎症反应的敏感性。我们假设位点特异性氧化和氧化应激的关键蛋白质传感器的硝化作用，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。该建议的重点是a）通过有效的修复和降解氧化蛋白质的正常细胞机制，这些机制可以维持细胞稳态，b）b）观察到的观察到年龄依赖性氧化修饰对CAM的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，因为巨噬细胞功能的年龄依赖性下降有助于免疫反应减少和非功能性细胞的积累，而无功能性细胞的清除对于健康衰老是必不可少的。此外，我们最近已经确定了CAM在介导巨噬细胞激活和自由基杀伤中的先前未识别的临界作用，该作用涉及通过iNOS激活和涉及涉及TNF依赖性途径的自分泌信号传导的氧化爆发调节。我们预计，氧化CAM分数的CAM抽象和相关年龄依赖性的增加会导致观察到的巨噬细胞功能下降。我们建议，与巨噬细胞启动有关的循环细胞因子TNF的丰度增加，与巨噬细胞启动相关的循环细胞因子诱导了长期氧化应激，从而导致通过CAM氧化巨噬细胞功能的年龄依赖性下降。我们设计了两个具体的目标：在AIM 1中，将在原始巨噬细胞中调节慢性炎症和修复蛋白的抽象。 1：确定炎症细胞因子如何影响与细胞功能关系的CAM氧化，修复和降解的动力学。 2：了解位点特异性氧化如何不同地调节CAM依赖性酶。