Immunometabolic regulation of bone inflammaging

项目概要 老年人多器官的年龄相关炎症和异位脂质积累与骨相关 损失、虚弱和慢性疾病。例如，骨骼和胸腺是主要的初级淋巴器官 在人类和小鼠模型中逐渐积累异位脂质和脂肪细胞。富有同情心的 神经系统（SNS）通过突触后局部释放儿茶酚胺来调节所有器官系统 囊泡以快速的方式形成，没有时间滞后来完成控制转录的事件 特定细胞因子或脂肪因子的激活或翻译后调节。释放的儿茶酚胺 脂肪酸氧化需要来自各个局部组织生态位的 SNS，而脂肪酸氧化过程在老年人中会受到损害。 该提案旨在解决的关键问题是：A）衰老如何导致体内异位脂质的积累 骨髓？ B) 异位脂质的增加是否是骨增加的关联触发因素 衰老过程中出现的炎症和骨质疏松症。 C) 可以预防骨质流失和异位堆积吗 通过针对免疫代谢串扰的机制来实现衰老？这些问题都源于我们 发现衰老与去甲肾上腺素（NE）降解增加有关，这是由于去甲肾上腺素升高所致 单胺氧化酶 A (MAOA)（一种儿茶酚胺降解酶）的表达。长期目标是 该项目旨在破译控制骨炎症的神经免疫串扰并以此为目标 机制开发新方法来维持或增强老年人的骨功能。

PROJECT SUMMARY Age-related inflammation and accumulation of ectopic lipid in multiple organs in elderly is associated with bone loss, frailty and chronic diseases. For example, bone and thymus are the major primary lymphoid organs that progressively accumulate ectopic lipid and adipocytes in humans and mouse models. The sympathetic nervous system (SNS) regulates all organ systems by localized release of catecholamines from post-synaptic vesicles in a rapid fashion without the time-lag required to complete events that control transcriptional activation or post-translational regulation of specific cytokines or adipokines. The catecholamines released from SNS in various local tissue niches is required for fatty acid oxidation, a process that is impaired in elderly. The key questions this proposal aims to address is: A) How does aging cause accumulation of ectopic lipid in bone marrow? B) Whether increase in ectopic lipid serves as an associative trigger for increase in bone inflammation and osteoporosis seen during aging. C) Can one prevent bone loss and ectopic accumulation in aging by targeting the mechanisms that link immune-metabolic crosstalk? These questions emanate from our discovery that aging is associated with increased degradation of norepinephrine (NE) due to elevated expression of Monoamine Oxidase A (MAOA), a catecholamine degradation enzyme. The long-term goal of this project is to decipher neuro-immune crosstalk that controls bone inflammation and to target this mechanism to develop new approaches to maintain or enhance bone function in elderly.