Harnessing the human monocyte system to improve surgical recovery

利用人类单核细胞系统改善手术康复

• 批准号: 10027267
• 负责人: Brice Gaudilliere
• 金额: $ 39.43万
• 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: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10027267
• 关键词: Acute; Biological; Biological Markers; Blunt Trauma; Cells; Clinical Data; Cytometry; Development; Elements; Epigenetic Process; Evaluation; Exposure to; Goals; Health Care Costs; Homing; Hormonal; Human; Immune; Immune Targeting; Immune response; Immune system; Immunologic Monitoring; Immunologics; Immunology; Infection; Inflammatory; Intervention; Metabolic; Neurocognitive Deficit; Operative Surgical Procedures; Opioid; Orthopedic Surgery procedures; Pain; Patient Monitoring; Patients; Persistent pain; Phenotype; Property; Proteomics; Quality of life; Recovery; Recovery of Function; Replacement Arthroplasty; Research; Resolution; Risk; Role; Scientist; Sepsis; Signal Transduction; Surgical Injuries; System; Techniques; Testing; Translational Research; Trauma; Traumatic Brain Injury; Traumatic injury; adverse outcome; functional disability; high dimensionality; improved; individual patient; innovation; monocyte; mouse model; multidisciplinary; patient population; phenotypic data; postoperative recovery; pre-clinical; programs; response; response to injury; surgery outcome; translational approach

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.

利用人类单核细胞系统改善手术恢复 在美国，每年有超过3000万患者接受一次大型手术。手术后患者的康复很高 可变，可能会因并发症，例如感染，疼痛和功能而严重损害 损害。但是，我们目前预测患者康复的方法锚定在临床上， 表型数据，表现不佳。手术损伤会产生多细胞免疫响应，当 失调，导致不良手术结果。在患者中深入研究人类免疫系统 接受手术是一种合乎逻辑和承诺的策略，旨在确定风险预测和 揭示可以探索以改善手术恢复的机制。 我们的研究计划利用接受手术患者的高维免疫学监测来识别 可靠的可修改免疫机制，可以准确预测患者的康复。这个Mira提案建立 在我们广泛的翻译研究中，表明人类单核细胞中包含的免疫反应 系统（HMS）与大量关节后的疼痛和功能恢复密切相关 外科手术。我们将追求三个相关但不重叠的目标，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响应手术，以确定 手术恢复病理生物学中的HMS。其次，我们将在手术前询问HMS 确定患者的手术前免疫状态是否确定手术恢复的过程。第三，我们会的 使用前临床小鼠手术模型使用反向翻译策略来测试是否“可药” 人类确定的免疫目标可以加速恢复。我们将使用以下创新和 多学科策略：1）使用单细胞响应手术的HMS高维分析 质量细胞仪（包括细胞表型的动态改变，归巢特性和效应子响应）； 2） 使用集成分析的患者HMS的细胞，表观遗传和蛋白质组学元素的鉴定 我们小组开发的管道； 3）评估单核细胞信号选择性调制的新目标 小鼠模型中的反应概括了人类免疫反应对手术的标志。 该提案的主要优势是研究相关患者人群中与创伤相关的免疫学的研究 临床科学家在床边有效开创了高内核免疫监测技术。 当前的计划着重于骨科手术后的疼痛和功能障碍。但是，我们将学习 可能在许多急性炎症条件下共享的基本机制（例如其他手术， 钝创伤或脑部损伤）。因此，我们将能够转向整合我们的发现 在更广泛的免疫，代谢和神经激素对损伤的反应中，并评估其他 创伤性损伤后的不良结果，例如感染，败血症或神经认知障碍。