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：
Benjamin Levi
金额：
$ 37.74万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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：
https://reporter.nih.gov/project-details/10267729
关键词：
Activities of Daily Living Address Affect Animal Model Anti-Inflammatory Agents Automobile Driving Biological Markers Blood Burn injury Cells Clinical Complex DNA DNA receptor Data Data Set Diagnosis Disease Event Excision FDA approved Goals Heterotopic Ossification Histologic Histones Human Hydroxychloroquine Image Incidence Infection prevention Inflammation Inflammatory Injury Innate Immune Response Internet Intervention Joints Kidney Laboratories Liver Mechanics Mediating Molecular Target Motion Movement Mus Myelogenous Neutrophilic Infiltrate Operative Surgical Procedures Outcome Pathologic Pathway interactions Patient Selection Patients Peroxidases Pharmacology Phenotype Physicians Play Process Prophylactic treatment Radiation Recurrence Reporting Risk Role Secondary to Severities Signal Transduction Site Standardization Stimulus Structure TLR9 gene Therapeutic Time Tissues Treatment Protocols Work bone cell free DNA cohort extracellular high risk hip replacement arthroplasty in vivo inhibitor/antagonist limb injury mouse model musculoskeletal injury neutrophil novel novel therapeutic intervention personalized care personalized medicine prevent prophylactic recruit targeted treatment tissue injury transcriptome transcriptomics treatment strategy wound

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.

项目摘要异位骨化（HO）是骨骼外骨的病理形成，发生在〜20％髋关节置换术，肌肉骨骼创伤或烧伤后的患者，而这种发病率增加到80％以上在高能量损伤的患者中，暗示了先天免疫反应的作用。标准化预防HO的治疗方案缺失，HO的手术切除无法恢复受伤前功能能力，并且复发风险很高。 ho，无论发生什么煽动事件，最常见的是在网站上形成流动性。一旦诊断出HO，医师就会限制受影响关节的运动以限制进展，然而，限制迁移率改变炎症和HO进展的机制仍然未知。进一步使治疗更加复杂的事实是，目前没有生物标志物可以指导临床医生患者的风险很高，因此应接受预防和何时开始治疗。因此，有很大的临床需要开发有效的，炎症的靶向HO疗法并验证生物标志物指导患者选择和精确的治疗时机。该建议将生成数据集这两个未满足的临床需要为HO提供更有效干预的突破。我们小组对HO损伤的最新新型动态分析已确定中性粒细胞表型为中心到何。具体而言，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（网）在HO中起关键作用。这是一个新颖的方面，天生的免疫反应如何为Ho做出了贡献。据报道，组织损伤促使形成网络以预防感染（原发性肠病）。 HO是独一无二的尚未研究的网。初步数据表明，关节的运动破坏了主要网诱导网的传播（次生肠病），对发展至关重要。我们发现了这部特定的小说机理是由Toll样受体9（TLR9）介导的，这是DNA复合物的已知受体。因此，我们提出TLR9是特定于HO的新型目标。目标1：评估网络作为预测HO形成的生物标志物的作用。我们将评估差分网与我们的鼠标模型中的非HO控制相比，HO中的形成和良好的人类患者中的形成 HO（髋关节置换术）有风险的队列检查损伤部位和全身净水平作为HO生物标志物。 AIM 2：表征通过TLR9特定于次级净形成的角色和治疗潜力 HO形成和进展中的信号传导。我们还将评估药理学TLR9抑制的能力和中性粒细胞特异性TLR9缺失，以减轻次要的小鼠模型中的次生肠病和HO。