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: 10024564
• 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/10024564
• 关键词: Acceleration; Acute; Acute-Phase Reaction; Adult; Age; Aging; Agreement; Amino Acids; Anti-Inflammatory Agents; 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; Immune system; 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; in vivo; indexing; inhibitor/antagonist; interest; macrophage; monocyte; mortality; neurotransmission; novel; prevent; receptor; response; sensor; stressor; 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 LCN2 可以抑制食欲。同时，已知LCN2 作为一种急性期反应蛋白，细菌感染后血清中的浓度大大增加。自从 Lcn2主要由成骨细胞表达，我们探讨了成骨细胞衍生的LCN2是否是早期传感器 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，炎症更加常见。我们的初步数据， 使用脂多糖（LPS）给药小鼠作为炎症反应模型，表明 炎症刺激后，脑源性信号迅速刺激成骨细胞分泌 LCN2 循环。成骨细胞中 LCN2 的释放受到谷氨酸的刺激并受到神经元的调节。这 随着年龄的增长，反应会受到损害，并且可能会随着年龄的增长而增加炎症易感性。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后续 具有抑制内毒素血症、器官损伤和死亡率的作用。根据这些和其他初步数据，我们 假设骨骼是一种急性炎症感应器官，可以发挥救生抗病毒作用 通过成骨细胞分泌 LCN2 产生炎症反应。为了检验这个假设，我们将 确定成骨细胞衍生的 LCN2 是年轻人和老年人发起先天免疫反应所必需的 成骨细胞特异性缺失 Lcn2 的成年小鼠以及 LPS、细菌感染和败血症模型； 使成骨细胞中的 Grik5 受体失活，并检查它是否阻止成骨细胞中 LCN2 的释放 炎症后的血清并加剧年轻小鼠和衰老小鼠的疾病；建立信令 起源于大脑的信号通路，在年轻人和衰老过程中通过成骨细胞释放 LCN2 老鼠。这些研究将定义骨作为急性炎症应激源和反应源的新功能， 描述大脑如何通过骨骼和 LCN2 协调快速反应来调节全身 伴随着衰老的炎症。