Integration of Immunologic Phenotyping with Computational Approaches to Predict Clinical Trajectory in Septic Patients

免疫表型分析与计算方法相结合来预测脓毒症患者的临床轨迹

• 批准号: 10708534
• 负责人: Anthony S Bonavia
• 金额: $ 41.85万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708534
• 关键词: Academic Medical Centers; Acute; Adjuvant Therapy; Affect; Applications Grants; Award; Biological Assay; Caring; Cell Separation; Cells; Cessation of life; Chronic; Clinical; Clinical Research; Complex; Critical Illness; Data; Development; Disease; Epidemic; Functional disorder; Goals; Grant; Health Care Costs; Human; Iatrogenesis; Immune; Immune System Diseases; Immune Tolerance; Immune response; Immunologic Adjuvants; Immunologics; Inflammation; Measurement; Medical; Microfluidics; Morbidity - disease rate; Myeloid Cells; Myeloid-derived suppressor cells; National Institute of General Medical Sciences; Operative Surgical Procedures; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Pre-Clinical Model; Preclinical Testing; Research; Research Personnel; Research Priority; Scientist; Secondary to; Sepsis; Syndrome; Techniques; Testing; Tissues; Translating; Whole Blood; burden of illness; cancer therapy; chronic infection; clinical care; clinical predictors; clinical risk; cytokine; human model; in vitro Model; metabolomics; mortality; novel; participant enrollment; point of care testing; prognostic; prognostic value; prospective; recruit; response; secondary infection; septic patients; tertiary care; theories; tool; transcriptomics; trial enrollment

Project Summary/Abstract Sepsis is a global epidemic with a high patient morbidity and mortality, and it accounts for staggering healthcare costs both within the US and worldwide. Clinicians caring for septic patients are unable to distinguish between septic patients who will rapidly recover and those patients who will develop a prolonged disease course marked by immune dysfunction, infectious complications, chronic critical illness (CCI) and death. This affects their ability to weigh the clinical risks versus benefits of immune-adjuvant therapy, in cases where sepsis is characterized by marked immune paralysis. The long-term research goals are (1) to develop novel, rapid and personalized tools with which to predict the prognostic trajectory of septic patients based on underlying immune phenotype, and (2) to integrate this information into the clinical care of septic patients. The subject of this proposal encompasses the first of these two goals, with objectives aligning with the NIGMS Sepsis Research priorities (NOT-GM-19-054). Specifically, we will continue recruitment into an ongoing, prospective, observational, clinical research trial enrolling patients suffering from acute sepsis at a tertiary care, academic medical center. We will utilize a combination of immune-based assays and computational approaches to (i) Validate the prognostic value of rapid, microfluidic cytokine analysis, following ex vivo stimulation of whole blood. Hypothesis: functional immune phenotyping can identify septic patients with subclinical immune paralysis who are prone to secondary infections. Approach: Quantitative analyses comparing cytokine responses to immune adjuvants before and after ex vivo stimulation of whole blood. Microfluidic cytokine analysis provides rapid and precise measurements and that are compatible with a clinical, point of care test. (ii) Compare the CCI syndrome following medical and surgical sepsis. Hypothesis: Iatrogenic tissue damage and inflammation caused by surgery alters the immune response and pathophysiology of CCI in surgical patients, as compared with medical patients. We will use a combination of transcriptomic and metabolomic data to confirm current theories of CCI pathophysiology in surgical patients, and then explore how it differs in patients having medical sepsis. (iii) Develop high fidelity, in vitro models of human myeloid-derived suppressor cells (MDSCs) with which to perform preclinical testing of potential therapies for sepsis-induced CCI. Hypothesis: human MDSCs (immature myeloid cells that expand during chronic infection and suppress immune responses) can be generated through differentiation from peripheral blood mononuclear cells isolated from whole blood. These cells can be used as a novel preclinical model with which to test potential therapies for CCI that are extrapolated from the treatment of cancer. The PI of this grant application is a clinician- scientist and the current recipient of a K08 award from the NIGMS which studies sepsis. He is ready to progress to scientific independence via the R-35 grant mechanism for early-stage investigators.

项目总结/摘要 脓毒症是一种全球性的流行病，发病率和死亡率高， 美国和世界范围内的医疗费用。照顾败血症患者的临床医生无法 区分迅速恢复的脓毒症患者和将发生长期 以免疫功能障碍、感染性并发症、慢性危重病（CCI）和 死亡这影响了他们权衡免疫辅助治疗的临床风险与益处的能力， 其中脓毒症的特征是明显的免疫麻痹。长期研究目标是：（1）开发 一种新颖、快速和个性化的工具，用于预测脓毒症患者的预后轨迹， 潜在的免疫表型，和（2）整合这些信息到脓毒症患者的临床护理。的 本提案的主题包括这两个目标中的第一个，其目标与国家地理信息系统相一致 脓毒症研究优先级（NOT-GM-19-054）。具体来说，我们将继续招聘到一个持续的， 前瞻性、观察性、临床研究试验，在三级护理中招募急性脓毒症患者， 学术医疗中心我们将利用基于免疫的测定和计算的组合， 方法（i）确定快速，微流控细胞因子分析的预后价值， 刺激全血。假设：功能性免疫表型可以识别脓毒症患者， 亚临床免疫瘫痪的人容易继发感染。方法：定量分析 比较全血离体刺激之前和之后对免疫佐剂的细胞因子应答。 微流体细胞因子分析提供了快速和精确的测量， 即时检验(ii)比较内科和外科脓毒症后的CCI综合征。假设：医源性 手术引起的组织损伤和炎症改变了CCI的免疫应答和病理生理学， 与内科患者相比，外科患者。我们将使用转录组学和 代谢组学数据，以确认手术患者CCI病理生理学的当前理论，然后探索如何 它在患有医学败血症的患者中是不同的。(iii)开发高保真的人骨髓源性体外模型 抑制细胞（MDSC），用于对脓毒症诱导的 CCI。假设：人类MDSC（未成熟的骨髓细胞，在慢性感染期间扩增，并抑制 免疫应答）可以通过从分离的外周血单核细胞分化产生 全血。这些细胞可以作为一种新的临床前模型来测试潜在的治疗方法 对于CCI是从癌症的治疗中推断出来的。这项拨款申请的主要研究者是一名临床医生- 科学家，目前获得NIGMS研究败血症的K 08奖。他准备 通过R-35赠款机制为早期研究人员提供科学独立性。