Substance P exacerbation of staphylococcal bone damage

P 物质加剧葡萄球菌骨损伤

基本信息

批准号：
10707224
负责人：
Morgan Brittany Johnson
金额：
$ 38.25万
依托单位：
UNIVERSITY OF NORTH CAROLINA CHARLOTTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-19 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10707224
关键词：
Acute Address Affinity Animal Model Anti-Inflammatory Agents Attenuated Bacteria Bacterial Infections Biological Biological Response Modifiers Bone Diseases Bone Resorption Bone Tissue Bone remodeling Cells Central Nervous System Chemotactic Factors Clinical Dendritic Cells Development Diagnosis Disease FDA approved Gastrointestinal tract structure Genus staphylococcus Goals Human Immune In Vitro Incidence Infection Inflammation Inflammation Mediators Inflammatory Leukocytes Macrophage Maintenance Mediating Mediator Microbe Mus Myeloid Cells Nerve Fibers Neuropeptide Receptor Neuropeptides Organism Osteitis Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteolytic Osteomyelitis Performance Peripheral Physiological Play Production Prophylactic treatment Regulation Research Role Sensory Severities Severity of illness Site Skin Staphylococcus aureus Substance P TACR1 gene Tachykinin Testing Therapeutic Therapeutic Intervention Tissues Work antagonist antimicrobial drug bone bone cell bone loss clinically relevant experimental study human model immune function improved in vivo inflammatory bone loss inhibitor microbial mouse model nerve supply neutrophil osteogenic pathogenic microbe preclinical evaluation prophylactic recruit response therapeutic target

项目摘要

Project Summary Bone disorders such as osteomyelitis that result from bacterial infection are associated with severe inflammation and progressive bone loss. Staphylococcus aureus is the most common causative agent of osteomyelitis and the incidence and severity of staphylococcal osteomyelitis appears to be increasing despite improvements in prophylaxis and diagnosis. Dysregulation of osteoclast formation and activity results in bone destruction and/or abnormal bone remodeling at sites of infection, and osteoblasts play an essential role in the regulation of these bone-resorbing cells. In addition, bacterially infected osteoblasts and osteoclasts are capable of producing an array of immune mediators that could promote the recruitment and activation of inflammatory leukocytes in bone tissue. The neuropeptide substance P (SP) is increasingly recognized to exacerbate inflammation in a range of tissues including the gut, skin, and central nervous system. Given the extensive innervation of bone tissue with SP- containing nerve fibers, the functional expression of the specific receptor for SP (NK-1R) by bone cells, and previous evidence that this neuropeptide can modulate bone cell responses, we suggest that SP/NK-1R interactions exacerbate inflammation in osteomyelitis. In this application, we propose a comprehensive preclinical evaluation of the ability of this neuropeptide to augment inflammation in isolated murine and human resident bone cells and an established in vivo animal model of staphylococcal osteomyelitis. This work builds upon our prior work and will test the hypothesis that inhibition of SP/NK-1R interactions attenuates the immune and osteolytic responses of resident bone cells to bacteria. Furthermore, these studies represent an essential step in evaluating the therapeutic potential of repurposing clinically approved NK-1R antagonists as an adjunctive therapy to limit staphylococcal osteomyelitis-associated inflammatory bone loss and/or abnormal bone remodeling, and may point to neurogenic input as a therapeutic target for the treatment of inflammatory bone disorders in general.

项目摘要细菌感染引起的骨髓炎等骨骼疾病与严重的炎症和进行性骨质流失。金黄色葡萄球菌是最大的骨髓炎的常见病因和发病率和严重程度尽管有所改善，葡萄球菌骨髓炎似乎正在增加预防和诊断。破骨细胞形成和活性的失调导致在感染部位的骨骼破坏和/或异常骨骼重塑，成骨细胞在调节这些骨呈现细胞中起着至关重要的作用。此外，细菌感染的成骨细胞和破骨细胞能够产生一个阵列可以促进炎症的募集和激活的免疫介质骨组织中的白细胞。神经肽物质P（SP）越来越多公认会加剧在肠道，皮肤和中枢神经系统。考虑到骨组织与SP-的广泛神经包含神经纤维，SP（NK-1R）的特定受体的功能表达通过骨细胞，并以前的证据表明该神经肽可以调节骨细胞回答，我们建议SP/NK-1R相互作用加剧了炎症骨髓炎。在此应用中，我们提出了对这种神经肽在孤立的鼠和人类中增加炎症的能力驻留骨细胞和葡萄球菌的体内动物模型骨髓炎。这项工作以我们先前的工作为基础，并将检验以下假设。 SP/NK-1R相互作用的抑制会减轻居民骨细胞到细菌。此外，这些研究代表了重要的步骤在评估重新利用临床认可的NK-1R的治疗潜力时拮抗剂作为一种辅助疗法，以限制葡萄球菌骨髓炎相关炎症性骨质流失和/或异常骨骼重塑，可能指向神经源性一般来说，输入是治疗炎症性骨骼疾病的治疗靶标。