Harnessing the human monocyte system to improve surgical recovery

利用人单核细胞系统改善手术恢复 在美国，每年有超过3000万患者接受大手术。患者术后恢复情况良好 可变的，并可能严重损害并发症，如感染，长期疼痛，和功能 损伤然而，我们目前预测患者恢复的方法是基于临床和 表型数据和表现不佳。手术损伤产生多细胞免疫反应，当 失调，导致不良的手术结果。深入研究人体免疫系统， 接受手术是一种合乎逻辑的和有前途的策略，以确定风险预测的生物特征， 揭示了可以用来改善手术恢复的机制。 我们的研究计划利用了接受手术的患者的高维免疫监测来识别 可修改的免疫机制，准确地预测病人的恢复。MIRA的建议建立 我们广泛的转化研究表明，人类单核细胞中含有的免疫反应， 系统（hMS）与主要关节置换术后疼痛缓解和功能恢复密切相关 手术我们将追求三个相互关联，但不重叠的目标，重点是hMS：首先，我们将评估 循环单核细胞的表型和功能动力学对手术的反应，以确定 hMS在手术恢复病理学中的应用其次，我们会在手术前询问hMS， 确定患者的术前免疫状态是否决定手术恢复的过程。三是 使用临床前小鼠手术模型的反向翻译策略来测试是否“可用药” 在人体内发现的免疫靶点可以加速康复。我们将采用以下创新和 多学科策略：1）使用单细胞免疫荧光技术对hMS响应于手术的高维特征进行分析， 质谱细胞计数（包括细胞表型、归巢特性和效应子应答的动态变化）; 2） 使用综合分析方法鉴定患者hMS的细胞、表观遗传和蛋白质组元件， 3）选择性调节单核细胞信号传导的新靶点的评价 在小鼠模型中的反应，概括了人类对手术的免疫反应的标志。 这项建议的一个主要优势是在相关的患者群体中研究创伤相关的免疫学， 一位临床医生兼科学家，他有效地开创了床边高含量免疫监测技术。 目前的计划侧重于骨科手术后的疼痛和功能障碍。但是，我们将研究 许多急性炎症性疾病可能共有的基本机制（例如，其他手术， 钝伤或创伤性脑损伤）。因此，我们将能够转向整合我们的研究结果， 在更广泛的免疫学、代谢和神经激素对损伤的反应以及对其他损伤的评估中， 创伤性损伤后的不良后果，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.