Myeloid lineage targeting to improve recovery from injury and surgery: Cellular and molecular mechanisms

骨髓谱系靶向改善损伤和手术恢复：细胞和分子机制

• 批准号: 10027000
• 负责人: Vivianne L Tawfik
• 金额: $ 40.13万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10027000
• 关键词: Acute Pain; Affect; Affective; American; CCL4 gene; Cell Lineage; Cells; Clinical; Complex; Etiology; Fracture Healing; Functional disorder; Human; Immune system; Impaired healing; Impairment; Individual; Injury; Innate Immune Response; Intervention; Knowledge; Ligands; Link; Microglia; Molecular; Molecular Profiling; Molecular Target; Monitor; Motivation; Myelogenous; Operative Surgical Procedures; Orthopedics; Pain; Perioperative; Peripheral; Persistent pain; Positioning Attribute; Positron-Emission Tomography; Recovery; Research; Risk; Spinal Cord; Surgical Injuries; Tissues; Transgenic Organisms; Trauma; Traumatic injury; Whole Organism; Work; Yolk Sac; attenuation; bone healing; bone imaging; cellular targeting; chronic pain; critical period; cytokine; disability; functional disability; healing; immune activation; improved; improved outcome; in vivo monitoring; injury recovery; macrophage; mouse model; new therapeutic target; novel marker; response; response to injury; serial imaging

Project Summary Despite the number of people affected each year by persistent pain and poorly healed fractures after nonfatal traumatic and surgical injury it remains unclear what are the key components of the profound multicellular response to injury and how they can be manipulated to improve outcomes. In particular, peripheral injury mobilizes the immune system to resolve tissue damage, however, sustained immune activation can be detrimental and contribute to delayed healing. Myeloid-lineage cells are instrumental in the innate immune response to injury- peripherally, as macrophages, and centrally, as yolk sac-derived microglia. Nevertheless, the temporal and compartment-specific contributions of myeloid-lineage cells to bone healing, perioperative pain and surgical recovery have yet to be elucidated. Precise manipulation of these myeloid-lineage cells to establish causation is not possible in humans. To identify cellular and molecular targets for improving recovery we will therefore take advantage of a clinically informed mouse model of orthopaedic injury. Our central hypothesis is that there is a critical period during which myeloid-lineage cell involvement is crucial for proper recovery from injury; however, prolonged activation, marked by cytokine release and loss of homeostatic functions, can contribute to pain and impaired bone healing ultimately increasing the risk for long-term disability. To pursue this fundamental work, we will use a combination of molecular and whole organism approaches in which we have significant expertise including mouse models of complex orthopaedic trauma, affective-motivational readouts of persistent pain and functional impairment, specific transgenic manipulations and longitudinal imaging of bone and CNS tissues. In particular, this convergence of capabilities uniquely positions us to answer the following key knowledge gaps: 1) The innate immune response is instrumental to recovery, but can its dysfunction be monitored in vivo to identify at risk individuals? 2) What specific molecular signatures of activated myeloid- lineage cells can be targeted peripherally and centrally to improve outcomes? 3) Is the myeloid-lineage response to peripheral injury evolutionarily conserved and therefore translationally relevant? The proposed research builds on our previous work in a mouse model of chronic pain in which we showed that: 1) Myeloid-targeted positron emission tomography ligands can track dysfunctional innate immune activation, 2) Attenuation of macrophage and microglial activation can improve persistent pain, 3) New markers can be used to distinguish infiltrating macrophages from resident microglia in the spinal cord thus clarifying their unique contributions. Ultimately, these studies will establish how myeloid-lineage cells may be the initial cellular link between peripheral injury, poor bone healing and severe acute pain. Successful completion of the proposed studies will enhance our understanding of compartment-specific macrophage and microglia effects on healing after injury, identify cell- specific targets for intervention, and clarify when and in whom such treatments will provide the most benefit.

项目摘要 尽管每年受到持续疼痛和非致命后骨折治愈不佳的人数 创伤性和手术损伤尚不清楚深层多细胞的关键组成部分是什么 对伤害的反应以及如何操纵它们以改善预后。特别是外围伤害 动员免疫系统解决组织损伤，但是，持续的免疫激活可能是 有害并导致延迟愈合。髓样细胞细胞在先天免疫中发挥了作用 对损伤的反应 - 外周，作为巨噬细胞，中央，作为蛋黄囊衍生的小胶质细胞。然而， 髓样系细胞对骨骼愈合，围手术期疼痛的时间和隔室特异性贡献 手术恢复尚未阐明。精确操纵这些髓样细胞以建立 人类不可能发生因果关系。为了鉴定细胞和分子靶标以改善恢复，我们将 因此，利用临床知情的骨科损伤的小鼠模型。我们的中心假设是 在一个关键时期，在此期间，髓样细胞的受累对于适当从中恢复至关重要 受伤;然而，长时间的激活，以细胞因子释放和稳态功能的损失为特征，可以 导致疼痛和骨骼愈合受损，最终增加了长期残疾的风险。追求这一点 基本工作，我们将使用分子和整个生物体方法的组合 重要的专业知识，包括复杂骨外科创伤的小鼠模型，情感动机读数 持续的疼痛和功能障碍，特定的转基因操纵和骨骼的纵向成像 和CNS组织。特别是，这种功能的融合唯一地定位了我们回答以下键 知识差距：1）先天免疫反应对恢复有用，但其功能障碍可以 在体内受到监测以识别处于风险的人吗？ 2）激活髓样的特定分子特异 谱系细胞可以在外围和集中靶向以改善预后？ 3）是髓样线反应 在进化上保守的外围损伤，因此在翻译上相关？拟议的研究建造 关于我们以前在慢性疼痛模型中的工作 排放层析成像配体可以跟踪功能失调的先天免疫激活，2）巨噬细胞的衰减 小胶质细胞激活可以改善持续性疼痛，3）可以使用新标记来区分浸润 脊髓中常驻小胶质细胞的巨噬细胞阐明了它们的独特贡献。最终， 这些研究将确定髓样细胞细胞如何成为外周损伤之间的初始细胞联系， 骨骼治愈不佳和严重的急性疼痛。成功完成拟议的研究将增强我们的 了解隔室特异性巨噬细胞和小胶质细胞对损伤后愈合的影响，鉴定细胞 干预的具体目标，并阐明何时及其中的治疗方法最大的好处。