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.

项目摘要/摘要 败血症是一种全球流行病，患者发病率高和死亡率，这是惊人的 美国和全球范围内的医疗保健费用。关心化粪池患者的临床医生无法 区分迅速康复的化粪池患者和那些会延长的患者 免疫功能障碍，传染性并发​​症，慢性危害疾病（CC​​I）和 死亡。这会影响他们权衡临床风险与免疫辅助治疗的益处的能力，如果 败血症以明显的免疫麻痹为特征。长期研究目标是（1） 新颖，快速和个性化的工具，可以根据这些工具来预测化粪池患者的预后轨迹 潜在的免疫表型，（2）将这些信息整合到化粪池患者的临床护理中。这 该提案的主题涵盖了这两个目标中的第一个，目标与纽格姆斯保持一致 败血症研究的重点（INT-GM-19-054）。具体而言，我们将继续招募持续 前瞻性，观察性，临床研究试验，在三级护理中招募患有急性败血症的患者， 学术医学中心。我们将利用基于免疫的测定和计算的组合 （i）验证快速微流体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化粪池患者 亚临床免疫瘫痪，容易发生继发感染。方法：定量分析 比较了全血之前和之后的细胞因子对免疫佐剂的反应。 微流体细胞因子分析提供了快速而精确的测量，并且与临床兼容 护理点测试。 （ii）比较医疗和手术败血症后的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的免疫反应和病理生理学 与医学患者相比，手术患者。我们将结合转录组和 代谢组数据确认手术患者中CCI病理生理学的当前理论，然后探索如何 患有脓毒症的患者有所不同。 （iii）形成高富度性，体外模型的人髓样衍生 抑制细胞（MDSC），用于对败血症诱导的潜在疗法进行临床前测试 CCI。假设：人MDSC（在慢性感染过程中膨胀并抑制的未成熟髓样细胞 免疫反应可以通过与外周血单核细胞分离而产生 从全血。这些细胞可以用作测试潜在疗法的新型临床前模型 对于从癌症治疗中推断的CCI。该赠款申请的PI是临床医生 - 科学家和目前从研究败血症的Nigms获得K08奖的获得者。他准备好了 通过R-35早期研究人员的R-35赠款机制发展到科学独立性。