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 持续的低度炎症是慢性疾病发展的基础， 老人脂肪组织对年龄相关的炎症表现出独特的易感性。即使是健康的人 在老年时积累内脏脂肪，导致全身炎症增加和代谢减少 健康老年脂肪组织炎症的一个强有力的候选来源是常驻免疫区室。 在每个器官内都有一个专门的免疫细胞库，这对组织的稳态至关重要 和压力适应。在脂肪组织中，常驻免疫细胞协调对禁食和寒冷的反应， 我们先前的工作证实，脂肪免疫细胞的变化会削弱对这两种免疫细胞的反应。 老老鼠的挑战但是，在整个过程中驱动脂肪驻留免疫功能障碍的机制 寿命仍然难以捉摸。该提案将利用新的技术方法来解决这一问题 悬而未决的问题。外周免疫细胞在衰老过程中积累细胞内缺陷，导致免疫功能低下。 接种疫苗或感染后的免疫保护。鉴于组织驻留免疫细胞在生命早期就被接种 并通过自我更新来维持，我们预计它们对与年龄有关的监管特别敏感。 压力重要的是，免疫细胞也对环境信号和细胞外细胞因子敏感， 营养素的可用性强烈影响免疫细胞的募集和功能。因此，我们假设 免疫细胞的内在和外在机制都会导致衰老的脂肪细胞调节失调， 免疫区室我们将使用一种诱导性的命运映射策略，结合血管内标记， 研究真正的长寿脂肪驻留免疫细胞。我们将使用基于病毒载体的邻近连接 一种发现脂肪分泌蛋白的年龄依赖性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的肥胖小鼠，我们将分离出年龄特异性的机制， 炎症和脂肪组织功能障碍。我们将利用这些结果来开发新的策略， 老化脂肪驻留免疫隔室和防止炎症。我们的方法克服了几个 衰老科学中长期存在的障碍：（1）知道免疫细胞的“年龄”，（2）精确定位已知的细胞 年龄相关细胞因子/分泌因子的来源。有了这些新功能，我们的工作将向前推进 衰老科学和使发现新的疾病机制影响任何器官系统。