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: 10632046
• 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/10632046
• 关键词: Acceleration; Acute; Acute-Phase Reaction; Aging; Agreement; Amino Acids; Anti-Inflammatory Agents; Bacteremia; Bacterial Infections; Blood; Bone Marrow; Bone Tissue; Brain; Cell Wall; Cells; Cellular Structures; Characteristics; Circulation; Data; Dendritic Cells; Desire for food; Disease; Elderly; Endocrine; Endotoxemia; Escherichia coli Infections; Event; Exhibits; 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; Macrophage; Mediating; Mediation; Metabolic; Modeling; Mus; N-Methyl-D-Aspartate Receptors; Natural Immunity; Neurons; Neuropeptides; Neurotransmitters; Organ; Osteoblasts; Osteocalcin; Phenotype; Play; Predisposition; Proteins; Role; Sense Organs; Sepsis; Serum; Signal Pathway; Signal Transduction; Stimulus; Stress; Time; Tissues; aging population; bone; cytokine; human old age (65+); in vivo; indexing; inhibitor; interest; 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 我们最近发现成骨细胞衍生的LCN 2抑制食欲。与此同时，LCN 2已知 作为急性期反应蛋白，在细菌感染后在血清中高度增加。以来 Lcn 2主要由成骨细胞表达，我们探讨了成骨细胞来源的LCN 2是否是一个早期传感器。 和炎症调节剂。在人口老龄化的背景下，这种反应特别令人感兴趣 免疫系统反应减弱，炎症更常见。我们的初步数据， 作为小鼠中给予脂多糖（LPS）的炎症反应模型，表明， 在炎症刺激后，脑源性信号迅速刺激成骨细胞分泌LCN 2， 流通成骨细胞释放LCN 2受到谷氨酸的刺激并受到神经元的调节。这 反应随着年龄的增长而受损，并且可能导致老年时的炎症易感性。循环 LCN 2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的免疫应答。 抑制内毒素血症、器官损伤和死亡的功能。根据这些和其他初步数据，我们 假设骨骼是一种急性炎症敏感器官， 通过成骨细胞分泌LCN 2的炎症反应。为了验证这个假设，我们将 使用年轻人和老年人建立成骨细胞衍生LCN 2是建立先天免疫应答所必需的 成骨细胞特异性缺失Lcn 2的成年小鼠以及LPS和细菌感染和脓毒症模型; 在成骨细胞中特异性地检测Grik 5受体，并检查它是否阻止LCN 2在成骨细胞中的释放。 炎症后的血清并加剧年轻成年人和衰老小鼠的疾病;建立信号传导 起源于大脑并在年轻成人和衰老中通过成骨细胞发出LCN 2释放信号的途径 小鼠这些研究将定义骨作为急性炎症应激源和反应器的新功能， 描述大脑如何通过骨骼和LCN 2协调快速反应，以调节系统性 炎症与衰老。