Neutrophil Biomarker and neutrophil targeted therapy to predict and prevent heterotopic ossification
中性粒细胞生物标志物和中性粒细胞靶向治疗可预测和预防异位骨化
基本信息
- 批准号:10267729
- 负责人:
- 金额:$ 37.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-21 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:Activities of Daily LivingAddressAffectAnimal ModelAnti-Inflammatory AgentsAutomobile DrivingBiological MarkersBloodBurn injuryCellsClinicalComplexDNADNA receptorDataData SetDiagnosisDiseaseEventExcisionFDA approvedGoalsHeterotopic OssificationHistologicHistonesHumanHydroxychloroquineImageIncidenceInfection preventionInflammationInflammatoryInjuryInnate Immune ResponseInternetInterventionJointsKidneyLaboratoriesLiverMechanicsMediatingMolecular TargetMotionMovementMusMyelogenousNeutrophilic InfiltrateOperative Surgical ProceduresOutcomePathologicPathway interactionsPatient SelectionPatientsPeroxidasesPharmacologyPhenotypePhysiciansPlayProcessProphylactic treatmentRadiationRecurrenceReportingRiskRoleSecondary toSeveritiesSignal TransductionSiteStandardizationStimulusStructureTLR9 geneTherapeuticTimeTissuesTreatment ProtocolsWorkbonecell free DNAcohortextracellularhigh riskhip replacement arthroplastyin vivoinhibitor/antagonistlimb injurymouse modelmusculoskeletal injuryneutrophilnovelnovel therapeutic interventionpersonalized carepersonalized medicinepreventprophylacticrecruittargeted treatmenttissue injurytranscriptometranscriptomicstreatment strategywound
项目摘要
Project Summary
Heterotopic ossification (HO) is the pathologic formation of extra-skeletal bone that occurs in ~20% of
patients after hip arthroplasty, musculoskeletal trauma or burns, whereas this incidence increases to over 80%
in patients with high energy injuries implicating the role of the innate immune response. Standardized
treatment protocols to prevent HO are missing and surgical resection of HO fails to restore pre-injury functional
capacity and has a high risk of recurrence. HO, regardless of the inciting event, most commonly forms at sites
of mobility. Once HO is diagnosed, physicians restrict movement of the effected joint to limit progression,
however, the mechanism behind limiting mobility to alter inflammation and HO progression remains unknown.
Further complicating treatment is the fact that there are currently no biomarkers to guide clinicians on which
patients are at high HO risk and therefore should receive prophylaxis and when to initiate treatment. Thus,
there is a substantial clinical need to develop an effective, inflammatory targeted HO therapy and to validate a
biomarker to guide patient selection and precise therapeutic timing. This proposal will generate data sets for
those two unmet clinical needs to provide a breakthrough towards more efficient intervention for HO.
Recent novel dynamic analyses of HO injuries by our group have identified neutrophil phenotype as central
to HO. Specifically, we found that structural components released by neutrophils, known as neutrophil
extracellular traps (NETs), play a critical role in HO. This is a novel aspect how the innate immune response
contributes to HO. It is reported that tissue injury prompts formation of NETs for prevention of infections
(primary NETosis). HO is unique as it forms in sites of mobility which adds a unique force (extrinsic) placed on
NETs which has not been studied. Preliminary data demonstrates that motion of a joint disrupts primary NETs
to induce propagation of NETs (secondary NETosis), critical to develop HO. We found this HO-specific novel
mechanism is mediated by toll-like receptor 9 (TLR9), a known receptor for DNA complexes. Therefore, we
propose that TLR9 is a novel target specific to HO.
Aim 1: Evaluate the role of NETs as a biomarker to predict HO formation. We will evaluate differential NET
formation in HO compared to non-HO control in our mouse models and in a well characterized human patient
cohort at risk for HO (hip arthroplasty) to examine injury site and systemic NET levels as a HO biomarker.
Aim 2: Characterize the role and therapeutic potential specific to secondary NET formation through TLR9
signaling in HO formation and progression. We will also assess the ability of pharmacologic TLR9 inhibition
and neutrophil specific Tlr9 deletion to mitigate secondary NETosis and HO in proven mouse models.
项目概要
异位骨化 (HO) 是骨骼外骨的病理形成,约 20% 的人发生
髋关节置换术、肌肉骨骼创伤或烧伤后的患者,而这种发生率增加到 80% 以上
涉及先天免疫反应作用的高能量损伤患者。标准化
缺乏预防 HO 的治疗方案,并且手术切除 HO 未能恢复损伤前的功能
容量大,复发风险高。 HO,无论煽动事件如何,最常见于现场形成
的流动性。一旦诊断出 HO,医生就会限制受影响关节的运动以限制进展,
然而,限制活动性以改变炎症和 HO 进展的机制仍不清楚。
使治疗更加复杂的是,目前没有生物标记物可以指导临床医生进行哪些治疗
患者处于 HO 风险较高,因此应接受预防并确定何时开始治疗。因此,
临床迫切需要开发一种有效的炎症靶向 HO 疗法并验证
指导患者选择和精确治疗时机的生物标志物。该提案将生成数据集
这两个未满足的临床需求为更有效地干预 HO 提供了突破。
我们小组最近对 HO 损伤进行的新颖动态分析已确定中性粒细胞表型是核心
到何。具体来说,我们发现中性粒细胞释放的结构成分,称为中性粒细胞
细胞外陷阱(NET)在 HO 中发挥着关键作用。这是先天免疫反应如何进行的一个新方面
对 HO 做出贡献。据报道,组织损伤促进NETs的形成以预防感染
(原发性网络病)。 HO 是独特的,因为它在移动部位形成,这增加了施加在其上的独特力(外在力)
NET尚未研究过。初步数据表明,关节的运动会扰乱初级网络
诱导 NET 的传播(继发性 NETosis),这对于形成 HO 至关重要。我们找到了这部HO特有的小说
该机制由 Toll 样受体 9 (TLR9) 介导,TLR9 是一种已知的 DNA 复合物受体。因此,我们
提出 TLR9 是 HO 特异性的新靶点。
目标 1:评估 NET 作为预测 HO 形成的生物标志物的作用。我们将评估差分NET
在我们的小鼠模型和特征明确的人类患者中,与非 HO 对照相比,HO 的形成
存在 HO(髋关节置换术)风险的队列,以检查损伤部位和全身 NET 水平作为 HO 生物标志物。
目标 2:通过 TLR9 表征继发性 NET 形成的特定作用和治疗潜力
HO 形成和进展中的信号传导。我们还将评估药理 TLR9 抑制的能力
中性粒细胞特异性 Tlr9 缺失可减轻经过验证的小鼠模型中的继发性 NETosis 和 HO。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Benjamin Levi其他文献
Benjamin Levi的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Benjamin Levi', 18)}}的其他基金
Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification - diversity supplement
机械感觉和基质结构对创伤性异位骨化细胞命运规范的影响 - 多样性补充
- 批准号:
10533903 - 财政年份:2021
- 资助金额:
$ 37.74万 - 项目类别:
Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification
机械感觉和基质结构对创伤性异位骨化细胞命运规范的影响
- 批准号:
10832255 - 财政年份:2021
- 资助金额:
$ 37.74万 - 项目类别:
Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification
机械感觉和基质结构对创伤性异位骨化细胞命运规范的影响
- 批准号:
10297550 - 财政年份:2021
- 资助金额:
$ 37.74万 - 项目类别:
Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification
机械感觉和基质结构对创伤性异位骨化细胞命运规范的影响
- 批准号:
10448303 - 财政年份:2021
- 资助金额:
$ 37.74万 - 项目类别:
Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification
机械感觉和基质结构对创伤性异位骨化细胞命运规范的影响
- 批准号:
10613582 - 财政年份:2021
- 资助金额:
$ 37.74万 - 项目类别:
Neutrophil Biomarker and neutrophil targeted therapy to predict and prevent heterotopic ossification
中性粒细胞生物标志物和中性粒细胞靶向治疗可预测和预防异位骨化
- 批准号:
10900159 - 财政年份:2020
- 资助金额:
$ 37.74万 - 项目类别:
Neutrophil Biomarker and neutrophil targeted therapy to predict and prevent heterotopic ossification
中性粒细胞生物标志物和中性粒细胞靶向治疗可预测和预防异位骨化
- 批准号:
10081442 - 财政年份:2020
- 资助金额:
$ 37.74万 - 项目类别:
Targeting Molecular and Cellular Mediators of Inflammation to Prevent Pathologic Cell Differentiation and Heterotopic Ossification
靶向炎症的分子和细胞介质以防止病理性细胞分化和异位骨化
- 批准号:
9906177 - 财政年份:2017
- 资助金额:
$ 37.74万 - 项目类别:
Targeting Molecular and Cellular Mediators of Inflammation to Prevent Pathologic Cell Differentiation and Heterotopic Ossific
靶向炎症的分子和细胞介质以防止病理性细胞分化和异位骨化
- 批准号:
10283122 - 财政年份:2017
- 资助金额:
$ 37.74万 - 项目类别:
Developing New Diagnostic and Timed, TAK1 Specific Treatment Strategies for Trauma Induced Heterotopic Ossification
为创伤引起的异位骨化开发新的诊断和定时 TAK1 特异性治疗策略
- 批准号:
9398623 - 财政年份:2017
- 资助金额:
$ 37.74万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 37.74万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 37.74万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 37.74万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 37.74万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 37.74万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 37.74万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 37.74万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 37.74万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 37.74万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 37.74万 - 项目类别:
Research Grant