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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：
10584278
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/10584278
关键词：
Acute Address Affinity Animal Model Anti-Inflammatory Agents Attenuated Bacteria Bacterial Infections Biological Biological Response Modifiers Bone Diseases Bone Tissue Bone remodeling Cells 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 Maintenance Mediating Mediator of activation protein Microbe Mus Myeloid Cells Nerve Fibers Neuraxis 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 Substance P Receptor Tachykinin Testing Therapeutic Therapeutic Intervention Tissues Work antagonist antimicrobial drug bone bone cell bone loss clinically relevant experimental study human model immune function in vivo inflammatory bone loss inhibitor macrophage 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.

项目总结