Immunometabolic regulation of bone inflammaging

项目摘要 老年人骨相关炎症和多器官异位脂质积聚与骨相关 损失、虚弱和慢性疾病。例如，骨和胸腺是主要的初级淋巴器官， 在人类和小鼠模型中，异位脂质和脂肪细胞逐渐积累。交感 神经系统（SNS）通过从突触后神经元局部释放儿茶酚胺来调节所有器官系统。 囊泡以快速的方式没有完成控制转录的事件所需的时滞 特异性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 从SNS在各种局部组织壁龛所需的脂肪酸氧化，这是一个过程，在老年人受损。 该提案旨在解决的关键问题是：A）衰老如何导致异位脂质的积累， 骨髓？B）异位脂质增加是否作为骨增加的相关触发因素 炎症和骨质疏松症。C）可以防止骨质流失和异位积累， 通过靶向免疫代谢串扰的机制来延缓衰老？这些问题源于我们的 发现衰老与去甲肾上腺素（NE）的降解增加有关， 单胺氧化酶A（MAOA），一种儿茶酚胺降解酶的表达。的长期目标 这个项目是为了破译控制骨骼炎症的神经免疫串扰， 机制，以开发新的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.