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Immunoengineering Strategies for Musculoskeletal Trauma

肌肉骨骼创伤的免疫工程策略

基本信息

批准号：
10155430
负责人：
ROBERT E GULDBERG
金额：
$ 48.26万
依托单位：
UNIVERSITY OF OREGON
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：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10155430
关键词：
Age Animal Model Animals Antibodies Autopsy Awareness Biological Markers Biological Response Modifiers Biomechanics Bone Regeneration Cause of Death Cells Clinic Clinical Clinical Treatment Complication Cytokine Receptors Data Development Diagnostic radiologic examination Effector Cell Environment Evaluation Flow Cytometry Gold Histologic Homeostasis Human Image Immune Immune response Immune system Immunization Immunologic Markers Immunomodulators Immunosuppression Immunosuppressive Agents Impairment Infection Inflammatory Intervention Knowledge Lead Length of Stay Ligands Malignant Neoplasms Modeling Molecular Molecular Target Monoclonal Antibodies Muscle Myeloid-derived suppressor cells Natural regeneration Opportunistic Infections Osteogenesis Outcome Patient-Focused Outcomes Patients Pre-Clinical Model Predisposition Proteomics Rattus Regenerative response Reporting Role Serum Suppressor-Effector T-Lymphocytes Survivors Testing Therapeutic Therapeutic Intervention Time Trauma Trauma patient Treatment Cost Work base bone cancer immunotherapy combat wound cost cytokine design disability dosage effector T cell experience healing immunoengineering immunoregulation improved improved outcome in vivo in vivo regeneration microCT mortality musculoskeletal injury nanoGold nanoparticle novel particle pre-clinical predictive marker predictive modeling regenerative regenerative treatment response biomarker restoration silibinin small molecule success targeted treatment trauma care treatment response treatment strategy

项目摘要

PROJECT SUMMARY Musculoskeletal trauma is highly prevalent in both combat-wounded and civilian patients, and despite advances in trauma care, mortality and complication rates remain remarkably high. Patients who do not respond to treatment or suffer from complications, experience poor healing, longer hospital stays, increased treatment costs, and prolonged disability. Recently, systemic immune dysregulation and immunosuppression has been implicated in the limited success of current intervention strategies and poor outcomes in trauma patients. Systemic immune dysregulation and immunosuppression results in decreased levels of circulating pro-inflammatory cytokines and a decrease in circulating immune effector cells, such as effector T cells. Another notable hallmark of systemic immune dysregulation is elevated levels of immune suppressor cells, including myeloid-derived suppressor cells (MDSCs). Our overall objectives are to investigate (i) how the development of systemic immune dysregulation and immunosuppression relates to functional bone regeneration and (ii) how systemic immunomodulation impacts the immune system and regenerative outcomes following severe musculoskeletal trauma. We will meet these objectives through the following specific aims. SPECIFIC AIM 1: Characterize the development of systemic immune dysregulation and immunosuppression in a pre-clinical composite trauma model and identify immunological markers predictive of poor healing. Using a composite bone/muscle trauma pre- clinical model, we will longitudinally characterize systemic immune dysregulation biomarkers via flow cytometry and multi-analyte serum proteomic profiling and then utilize nonlinear evolutionary multivariate analytics to develop predictive models of functional bone regeneration. SPECIFIC AIM 2: Fabricate and optimize an immunomodulatory therapeutic to target and deplete MDSCs. We will develop synthetic gold nanoparticles functionalized with both Fc-mimicking and MDSC-targeting ligands that can mimic mAb function (SNAbs) and optimize their multivalency, Janus orientation, and size for MDSC depletion. SPECIFIC AIM 3: Evaluate the effect of systemic immunomodulation on the immune system status and bone regeneration in vivo following severe musculoskeletal trauma. We will test the hypothesis that targeted depletion of MDSCs will restore immune homeostasis and promote functional bone regeneration.

项目总结