Discovering mechanisms of tissue-resident immune aging

发现组织驻留免疫衰老的机制

• 批准号: 10472369
• 负责人: Emily Lauren Goldberg
• 金额: $ 145.35万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-08 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472369
• 关键词: Address; Adipose tissue; Affect; Age; Aging; Cells; Chronic Disease; Cues; Defect; Development; Disease; Elderly; Fasting; Functional disorder; Health; Homeostasis; Immune; Immune System Diseases; Impairment; Individual; Infection; Inflammaging; Inflammation; Label; Life; Ligation; Longevity; Metabolic; Methods; Mus; Nutrient; Obese Mice; Obesity; Organ; Peripheral; Predisposition; Proteins; Science; Source; Stress; Testing; Tissues; Vaccination; Viral Vector; Visceral; Work; age related; aged; base; biological adaptation to stress; body system; cytokine; extracellular; immune function; new technology; preservation; pressure; prevent; recruit; response; self-renewal; systemic inflammatory response

Project Summary Persistent low-grade inflammation underlies the development of chronic diseases that are prevalent in the elderly. Adipose tissue displays unique susceptibility to age-related inflammation. Even healthy individuals accumulate visceral adiposity in older age, leading to increased systemic inflammation and reduced metabolic health. A strong candidate source of inflammation in aged adipose tissue is the resident immune compartment. Within every organ is a specialized repertoire of resident immune cells that is essential for tissue homeostasis and stress adaptation. In adipose tissue, resident immune cells coordinate responses to fasting and cold, and our prior work establishes that changes in adipose-resident immune cells impairs responses to both these challenges in old mice. But the mechanisms that drive adipose-resident immune dysfunction throughout the lifespan have remained elusive. This proposal will leverage new technological approaches to address this outstanding question. Peripheral immune cells accumulate intracellular defects during aging, leading to poor immune protection after vaccination or infection. Given that tissue-resident immune cells are seeded early in life and maintained through self-renewal, we expect them to be especially sensitive to age-related regulatory pressures. Importantly, immune cells are also sensitive to environmental cues, and extracellular cytokines and nutrient availability strongly influence the recruitment and function of immune cells. Therefore, we hypothesize that both immune cell-intrinsic and -extrinsic mechanisms cause dysregulation of the aging adipose-resident immune compartment. We will use an inducible fate-mapping strategy, combined with intra-vascular labeling, to study bonafide long-lived adipose-resident immune cells. We will use a viral vector-based proximity ligation approach to discover age-dependent changes in adipose secreted proteins and test how they impact resident immune cells. By comparing old and younger obese mice, we will isolate age-specific mechanisms of inflammation and adipose tissue dysfunction. We will use these results to develop new strategies that protect the aging adipose-resident immune compartment and prevent inflammation. Our methods overcome several longstanding obstacles in aging science: (1) knowing the “age” of an immune cell, and (2) pinpointing known cell sources of age-associated cytokines/secreted factors. With these new capabilities, our work stands to advance aging science and enable discovery of new disease mechanisms affecting any organ system.

项目摘要 持续的低级感染是慢性疾病的发展，而慢性疾病在 老年。脂肪组织表现出对年龄相关炎症的独特敏感性。甚至健康的人 在老年年龄积累内脏肥胖，导致全身性炎症增加和代谢减少 健康。老年脂肪组织中炎症的强大候选来源是居民免疫室。 每个器官内是居民免疫小球的专业曲目，这对于组织稳态必不可少 和压力适应。在脂肪组织中，居民免疫小球协调对禁食和冷的反应，以及 我们先前的工作确定，脂肪居住的免疫小球的变化会损害对这两者的反应 老鼠的挑战。但是在整个过程中驱动脂肪居住的免疫功能障碍的机制 寿命仍然难以捉摸。该建议将利用新的技术方法来解决这个问题 出色的问题。外周免疫细胞在衰老期间积累细胞内缺陷，导致不良 疫苗接种或感染后的免疫保护。鉴于组织居住的免疫细胞在生命早期播种 并通过自我更新维持，我们希望它们对与年龄有关的调节特别敏感 压力。重要的是，免疫细胞也对环境线索，细胞外细胞因子和 养分的可用性强烈影响免疫球的募集和功能。因此，我们假设 免疫电池intrinsic和 - 超支机制都会引起脂肪居民的失调 免疫室。我们将使用可诱导的命运映射策略，并结合血管内标签， 研究真正的长寿命脂肪居住的免疫小球。我们将使用基于病毒载体的接近结扎 发现依赖年龄的脂肪分泌蛋白质变化并测试它们如何影响居民的方法 免疫细胞。通过比较老年和年轻肥胖小鼠，我们将隔离 炎症和脂肪组织功能障碍。我们将使用这些结果来制定保护的新策略 老化的脂肪居民免疫室并防止炎症。我们的方法克服了几个 老化科学中的长期障碍：（1）知道免疫核管的“年龄”，以及（2）指出已知细胞 与年龄相关的细胞因子/分泌因素的来源。有了这些新功能，我们的工作将有助于进步 老化科学并能够发现影响任何器官系统的新疾病机制。