Substance P exacerbation of staphylococcal bone damage
Substance P exacerbation of staphylococcal bone damage
批准号:
10707224
负责人:
Morgan Brittany Johnson
金额:
$38.25万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-19 至 2027-07-31
关键词:
AcuteAddressAffinityAnimal ModelAnti-Inflammatory AgentsAttenuatedBacteriaBacterial InfectionsBiologicalBiological Response ModifiersBone DiseasesBone ResorptionBone TissueBone remodelingCellsCentral Nervous SystemChemotactic FactorsClinicalDendritic CellsDevelopmentDiagnosisDiseaseFDA approvedGastrointestinal tract structureGenus staphylococcusGoalsHumanImmuneIn VitroIncidenceInfectionInflammationInflammation MediatorsInflammatoryLeukocytesMacrophageMaintenanceMediatingMediatorMicrobeMusMyeloid CellsNerve FibersNeuropeptide ReceptorNeuropeptidesOrganismOsteitisOsteoblastsOsteoclastsOsteocytesOsteogenesisOsteolyticOsteomyelitisPerformancePeripheralPhysiologicalPlayProductionProphylactic treatmentRegulationResearchRoleSensorySeveritiesSeverity of illnessSiteSkinStaphylococcus aureusSubstance PTACR1 geneTachykininTestingTherapeuticTherapeutic InterventionTissuesWorkantagonistantimicrobial drugbonebone cellbone lossclinically relevantexperimental studyhuman modelimmune functionimprovedin vivoinflammatory bone lossinhibitormicrobialmouse modelnerve supplyneutrophilosteogenicpathogenic microbepreclinical evaluationprophylacticrecruitresponsetherapeutic target
中文摘要
项目概要
由细菌感染引起的骨疾病(例如骨髓炎)与
伴有严重炎症和进行性骨质流失。金黄色葡萄球菌是最多的
骨髓炎的常见病原体及其发病率和严重程度
尽管情况有所改善,但葡萄球菌性骨髓炎似乎仍在增加
预防和诊断。破骨细胞形成和活性失调导致
感染部位的骨破坏和/或骨重塑异常以及成骨细胞
在这些骨吸收细胞的调节中发挥重要作用。此外,
受细菌感染的成骨细胞和破骨细胞能够产生一系列
免疫介质可以促进炎症的募集和激活
骨组织中的白细胞。神经肽物质 P (SP) 越来越多地被
公认会加剧一系列组织的炎症,包括肠道、皮肤和
中枢神经系统。鉴于 SP- 骨组织的广泛神经支配
含有神经纤维,SP特异性受体(NK-1R)的功能表达
由骨细胞产生,之前的证据表明这种神经肽可以调节骨细胞
反应,我们认为 SP/NK-1R 相互作用会加剧炎症
骨髓炎。在此应用中,我们提出了全面的临床前评估
这种神经肽增强离体小鼠和人类炎症的能力
常驻骨细胞和已建立的葡萄球菌体内动物模型
骨髓炎。这项工作建立在我们之前的工作基础上,并将检验以下假设:
抑制 SP/NK-1R 相互作用会减弱免疫和溶骨反应
常驻骨细胞对细菌的影响。此外,这些研究代表了重要的一步
评估重新利用临床批准的 NK-1R 的治疗潜力
拮抗剂作为辅助治疗来限制葡萄球菌骨髓炎相关的
炎症性骨质流失和/或骨重塑异常,并可能指向神经源性
一般而言,输入作为治疗炎症性骨疾病的治疗靶点。
英文摘要
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.
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Substance P exacerbation of staphylococcal bone damage
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批准号:10584278
-
项目类别:
-
资助金额:$38.25万
-
财政年份:2022
-
负责人:Morgan Brittany Johnson
-
依托单位:
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批准号:10452116
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项目类别:
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资助金额:$7.55万
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财政年份:2022
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负责人:Morgan Brittany Johnson
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依托单位:
Molecular mechanisms underlying glial inflammatory responses to Neisseria meningitidis: A pilot study
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批准号:10551245
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项目类别:
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资助金额:$7.55万
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财政年份:2022
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负责人:Morgan Brittany Johnson
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依托单位:
RIG-I as a therapeutic target for bacterial CNS infection: A pilot study
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批准号:10303500
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项目类别:
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资助金额:$15.1万
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财政年份:2021
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负责人:Morgan Brittany Johnson
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依托单位:
海外基金