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.

项目总结