Immunometabolic regulation of bone inflammaging

骨炎症的免疫代谢调节

• 批准号: 10641819
• 负责人: VISHWA DEEP DIXIT
• 金额: $ 46.16万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641819
• 关键词: Address; Adipocytes; Adipose tissue; Age; Aging; Biological Availability; Bone Marrow; Catecholamines; Cells; Chronic; Chronic Disease; Coupled; Data; Disease; Down-Regulation; Elderly; Enzymes; Event; Fatty acid glycerol esters; Fracture; Generations; Goals; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hydrolysis; Immune; Immune system; Impairment; Inflammaging; Inflammasome; Inflammation; Knock-in; Knockout Mice; Link; Lipids; Lipolysis; LoxP-flanked allele; Macrophage; Marrow; Mediating; Membrane; Metabolic; Metabolic dysfunction; Monoamine Oxidase A; Mus; Myeloid Cells; Nerve; Nerve Degeneration; Neuroimmune; Norepinephrine; Obesity; Organ; Osteitis; Osteoclasts; Osteoporosis; Post-Translational Regulation; Process; Radiation; Regulation; Research; Sympathetic Nervous System; Synaptic Vesicles; Testing; Thymus Gland; Time; Tissues; Transcriptional Activation; Transcriptional Regulation; Transgenic Mice; Triglycerides; Tyrosine 3-Monooxygenase; adipokines; age related; aged; body system; bone; bone health; bone loss; bone strength; cortical bone; cytokine; disability; fatty acid oxidation; frailty; healthspan; human model; immune reconstitution; improved; mass spectrometric imaging; mouse model; nerve supply; novel strategies; postsynaptic; prevent; primary lymphoid organ; protein expression; regenerative; skeletal; stem cell engraftment; substantia spongiosa; success

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.

项目摘要 年龄相关的炎症和异位脂质在多个器官中的积累与骨骼有关 损失，脆弱和慢性疾病。例如，骨和胸腺是主要的主要淋巴器官 逐渐积累人类和小鼠模型中的异位脂质和脂肪细胞。同情 神经系统（SNS）通过局部释放儿茶酚胺从后突触后调节所有器官系统 囊泡以快速的方式而没有完成转录转录的事件所需的时间段 特定细胞因子或脂肪因子的激活或翻译后调节。儿茶酚胺发布 脂肪酸氧化需要各种局部组织壁ni的SN，这一过程在老年人中受到损害。 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）异位脂质的增加是否是骨骼增加的关联触发因素 衰老期间出现炎症和骨质疏松症。 c）可以防止骨质流失和异位积累 通过靶向将免疫代谢串扰联系起来的机制来衰老？这些问题源于我们 发现衰老与由于升高而导致去甲肾上腺素（NE）的降解有关 单胺氧化酶A（MAOA）的表达，一种儿茶酚胺降解酶。长期目标 该项目是破译控制骨骼炎症的神经免疫串扰，并针对这一点 开发新方法以维持或增强老年人骨功能的机制。