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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.

项目总结