Bone as a regulator and responder to acute inflammation throughout life

骨骼作为一生中急性炎症的调节器和反应器

• 批准号: 10417243
• 负责人: STAVROULA KOUSTENI
• 金额: $ 55.13万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417243
• 关键词: Acceleration; Acute; Acute-Phase Reaction; Adult; Aging; Agreement; Amino Acids; Anti-Inflammatory Agents; Bacteremia; Bacterial Infections; Blood; Blood Circulation; Bone Marrow; Bone Tissue; Brain; Cell Wall; Cells; Cellular Structures; Characteristics; Data; Dendritic Cells; Desire for food; Disease; Endocrine; Endotoxemia; Escherichia coli Infections; Event; Exhibits; Ganglia; Ganglionic Blockers; Glutamate Transporter; Glutamates; Goals; Gram-Negative Bacteria; Hormones; Hour; Immune; Immune response; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Kainic Acid Receptors; LCN2 gene; Lactate Dehydrogenase; Life; Lipopolysaccharides; Mediating; Mediation; Metabolic; Modeling; Mus; N-Methyl-D-Aspartate Receptors; Natural Immunity; Neurons; Neuropeptides; Neurotransmitters; Organ; Osteoblasts; Osteocalcin; Phenotype; Play; Predisposition; Proteins; Role; Savings; Sense Organs; Sepsis; Serum; Signal Pathway; Signal Transduction; Stimulus; Stress; Time; Tissues; aging population; base; bone; cytokine; human old age (65+); in vivo; indexing; inhibitor; interest; macrophage; monocyte; mortality; neurotransmission; novel; prevent; receptor; response; sensor; stressor; systemic inflammatory response; transmission process; young adult

Project Summary – Project #2 We have recently shown that osteoblast-derived LCN2 suppresses appetite. At the same time, LCN2 is known as an acute phase response protein that following bacterial infections is highly increased in the serum. Since Lcn2 is primarily expressed by osteoblasts, we explored, whether osteoblast-derived LCN2 is an early sensor and regulator of inflammation. This response is of particular interest within the context of the aging population in which immune system responses are weakened and inflammation more common. Our preliminary data, using as a model of inflammatory response lipopolysaccharides (LPS) administration in mice, indicate that following an inflammatory stimulus, brain-derived signals rapidly stimulate osteoblasts to secrete LCN2 in the circulation. Release of LCN2 from osteoblasts is stimulated by glutamate and is regulated neuronally. This response is compromised with aging and may contribute to inflammation susceptibility with old age. Circulating LCN2 acts on key immune cells of the blood and other tissues and modulates their phenotype and subsequent function to contain endotoxemia, organ damage, and mortality. Based on these and other preliminary data, we hypothesize that bone is an acute inflammation-sensing organ that mounts lifesaving anti- inflammatory responses through LCN2 secretion by osteoblasts. To examine this hypothesis we will establish that osteoblast-derived LCN2 is required for mounting innate immune response using young and old adult mice with osteoblast-specific deletion of Lcn2 and models of LPS and bacterial infection and sepsis; inactivate the Grik5 receptor specifically in osteoblasts and examine whether it prevents LCN2 release in the serum after inflammation and exacerbates disease in young adult and in aging mice; establish the signaling pathway that originates in the brain and signals the release of LCN2 by osteoblasts in young adult and in aging mice. These studies will define a new function of bone as an acute inflammatory stressor and responder and delineate how the brain orchestrates a rapid response through bone and LCN2 to regulate systemic inflammation with aging.

项目摘要 - 项目＃2 我们最近表明，成骨细胞衍生的LCN2抑制了食欲。同时，LCN2是已知的 作为一种急性相反应蛋白，血清中菌株感染后的高度增加。自从 LCN2主要由成骨细胞表达，我们探索了成骨细胞衍生的LCN2是否是早期传感器 和炎症调节剂。在老龄化的情况下，这种反应特别感兴趣 其中免疫系统反应削弱了，炎症更为普遍。我们的初步数据， 用作小鼠炎性反应脂多糖（LPS）的炎症反应模型，表明 炎症刺激后，大脑衍生的信号迅速刺激成骨细胞，以分泌LCN2 循环。谷氨酸刺激从成骨细胞中释放LCN2，并受到神经元的调节。这 衰老会损害反应，并可能导致老年炎症敏感性。循环 LCN2作用于血液和其他组织的关键免疫细胞，并调节其表型和随后 功能可容纳内毒素血症，器官损伤和死亡率。基于这些和其他初步数据，我们 假设骨骼是一种急性发炎的器官 通过成骨细胞分泌LCN2分泌的炎症反应。为了审查这一假设，我们将 确定使用年轻人和老年人安装先天免疫反应需要成骨细胞衍生的LCN2 LCN2的成骨细胞特异性缺失以及LPS和细菌感染和败血症模型的成年小鼠； 使Grik5受体专门在成骨细胞中灭活，并检查它是否防止LCN2释放 炎症后的血清，使年轻成人和衰老小鼠的疾病加剧；建立信号 起源于大脑的途径，并信号在年轻人和衰老中通过成骨细胞释放LCN2 老鼠。这些研究将定义骨骼的新功能，为急性炎症压力源和响应者， 描述大脑如何通过骨骼和LCN2进行快速响应以调节全身性 随着衰老的炎症。