Harnessing the human monocyte system to improve surgical recovery

利用人类单核细胞系统改善手术恢复 在美国，每年有超过3000万名患者接受大手术。患者术后恢复率高 易受感染、持续疼痛和功能性疾病等并发症的影响。 减损。然而，我们目前预测患者康复的方法是基于临床和 表型数据和表现不佳。手术损伤会产生多细胞免疫反应，当 失控，会导致不良的手术结果。在患者身上深入检查人类免疫系统 手术是一种合理而有希望的策略，可以识别用于风险预测的生物特征，并 揭示了可以用来改善手术恢复的机制。 我们的研究项目利用手术患者的高维免疫监测来识别 可修改的免疫机制，可准确预测患者的康复。这项米拉提案建立了 我们广泛的翻译研究表明，人类单核细胞中包含的免疫反应 系统(HMS)与主要关节置换术后疼痛的缓解和功能恢复密切相关 做手术。我们将追求三个相互关联但不重叠的目标，重点放在HMS上：首先，我们将评估 循环单核细胞表型和功能动态变化在手术反应中的作用 HMS在手术康复病理生物学中的作用。其次，我们将在手术前审问HMS 确定患者的术前免疫状态是否决定了手术恢复的进程。第三，我们将 使用反向翻译策略，使用临床前的小鼠手术模型来测试是否可以用药 在人类身上识别的免疫靶点可以加速恢复。我们将使用以下创新和 多学科策略：1)使用单细胞对手术后的HMS进行高维分析 质量细胞术(包括细胞表型、归巢特性和效应反应的动态变化)；2) 应用综合分析鉴定患者HMS的细胞、表观遗传学和蛋白质组学成分 3)单核细胞信号选择性调控新靶点的评价 小鼠模型中的反应，概括了人类对手术的免疫反应的特征。 这一建议的一个主要优点是通过以下方式在相关患者群体中研究创伤相关免疫学 一位临床医生兼科学家，他在床边有效地开创了高含量免疫监测技术。 目前的计划重点是骨科手术后的疼痛和功能障碍。不过，我们会研究 可能在许多急性炎症情况下共享的基本机制(例如，其他手术， 钝性创伤或创伤性脑损伤)。因此，我们将能够转向整合我们的调查结果 在更广泛的免疫学、新陈代谢和神经激素对损伤的反应和其他 创伤后的不良后果，如感染、败血症或神经认知障碍。

Harnessing the human monocyte system to improve surgical recovery Over 30 million patients undergo a major surgery annually in the US. Patients’ recovery after surgery is highly variable and can be severely compromised by complications, such as infections, prolonged pain, and functional impairment. However, our current approaches to predict a patient’s recovery are anchored in clinical and phenotypical data and perform poorly. Surgical injury produces a multi-cellular immune response that, when dysregulated, leads to adverse surgical outcomes. Examining the human immune system in depth, in patients undergoing surgery is a logical and promising strategy to identify biological signatures for risk prediction and to reveal mechanisms that can be exploited to improve surgical recovery. Our research program utilizes the high-dimensional immune monitoring of patients undergoing surgery to identify modifiable immunological mechanisms that accurately predict a patient’s recovery. This MIRA proposal builds on our extensive translational research indicating that immune responses contained in the human Monocyte System (hMS) strongly correlate with pain resolution and functional recovery after major joint replacement surgery. We will pursue three inter-related, but non-overlapping goals focusing on the hMS: First, we will assess the phenotypic and functional dynamics of circulating monocytes in response to surgery to determine the role of the hMS in the pathobiology of surgical recovery. Second, we will interrogate the hMS before surgery to determine whether patients’ pre-surgical immune states determine the course of surgical recovery. Third, we will use a reverse translational strategy using a pre-clinical mouse model of surgery to test whether “druggable” immunological targets identified in humans can accelerate recovery. We will use the following innovative and multidisciplinary strategies: 1) high-dimensional profiling of the hMS in response to surgery using single-cell mass cytometry (including dynamic alterations in cell phenotype, homing properties and effector responses); 2) identification of cellular, epigenetic and proteomic elements of a patient’s hMS, using an integrative analytical pipeline developed by our group; 3) evaluation of new targets for selective modulation of monocyte signaling responses in a mouse model that recapitulates hallmarks of the human immune response to surgery. A major strength of this proposal is the study of trauma-related immunology in a pertinent patient population by a clinician-scientist who has effectively pioneered high-content immune monitoring techniques at the bedside. The current program focuses on pain and functional impairment after orthopedic surgery. However, we will study fundamental mechanisms that are likely shared across many acute inflammatory conditions (e.g. other surgeries, blunt trauma or traumatic brain injuries). As such, we will be able to pivot towards the integration of our findings within the broader immunologic, metabolic, and neuro-hormonal responses to injury and the evaluation of other adverse outcomes after traumatic injury, such as infections, sepsis, or neuro-cognitive impairment.