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: 10449251
• 负责人: Vivianne L Tawfik
• 金额: $ 40.15万
• 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/10449251
• 关键词: Acute Pain; Affect; Affective; American; CCL4 gene; Cell Lineage; Cells; Clinical; Complex; Etiology; 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; Persons; 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 fracture repair; 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.

项目概要 尽管每年都有许多人在非致命性骨折后受到持续性疼痛和骨折愈合不良的影响 外伤和手术损伤目前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来改善结果。特别是周围损伤 动员免疫系统来解决组织损伤，然而，持续的免疫激活可以 有害并导致延迟愈合。髓系细胞在先天免疫中发挥重要作用 对损伤的反应——外周为巨噬细胞，中枢为卵黄囊衍生的小胶质细胞。尽管如此， 髓系细胞对骨愈合、围手术期疼痛的颞叶和骨室特异性贡献 以及手术恢复情况尚未明确。精确操作这些骨髓系细胞以建立 因果关系在人类中是不可能的。为了确定改善恢复的细胞和分子目标，我们将 因此，利用临床知情的骨科损伤小鼠模型。我们的中心假设是 存在一个关键时期，在此期间髓系细胞的参与对于从疾病中正确恢复至关重要 受伤;然而，以细胞因子释放和稳态功能丧失为标志的长期激活可以 导致疼痛和骨骼愈合受损，最终增加长期残疾的风险。为了追求这个 基础工作中，我们将结合分子和整个有机体的方法，其中我们有 重要的专业知识，包括复杂骨科创伤的小鼠模型、情感动机读数 持续性疼痛和功能障碍、特定转基因操作和骨纵向成像 和中枢神经系统组织。特别是，这种能力的融合使我们能够独特地回答以下关键问题 知识差距：1）先天免疫反应有助于恢复，但其功能障碍是否可以通过 进行体内监测以识别高危人群？ 2) 激活的骨髓有哪些具体的分子特征- 可以针对外周和中枢谱系细胞来改善结果吗？ 3) 是髓系反应 外周损伤在进化上是保守的，因此具有转化相关性？拟议的研究构建 我们之前在慢性疼痛小鼠模型中的工作表明：1）骨髓靶向正电子 发射断层扫描配体可以追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）新标记物可用于区分浸润性疼痛 来自脊髓中小胶质细胞的巨噬细胞，从而阐明了它们独特的贡献。最终， 这些研究将确定髓系细胞如何成为外周损伤之间的初始细胞联系， 骨骼愈合不良和严重的急性疼痛。成功完成拟议的研究将增强我们的能力 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，识别细胞 干预的具体目标，并明确此类治疗何时以及对谁能带来最大益处。