Immune Signatures and Clinical Outcomes in Acute Pancreatitis

急性胰腺炎的免疫特征和临床结果

• 批准号: 10568011
• 负责人: Adam Lacy-Hulbert
• 金额: $ 75.76万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-04 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568011
• 关键词: Academic Medical Centers; Admission activity; Ancillary Study; Angiopoietin-2; Automobile Driving; Bioinformatics; Blood Tests; Blood Urea Nitrogen; Blood specimen; Cells; Clinical; Clinical Trials; Communities; Cytometry; Dedications; Development; Disease; Educational workshop; Enrollment; Event; Frequencies; Funding; Future; Gastrointestinal Diseases; Gene Expression Profile; Grant; HGF gene; Helper-Inducer T-Lymphocyte; Hospitalization; Hospitals; Hour; Human; Immune; Immune Targeting; Immunologics; Immunologist; Immunology; Immunotherapeutic agent; Immunotherapy; In Vitro; Inflammatory Response; Insulin-Dependent Diabetes Mellitus; Intensive Care Units; Interleukin-8; Intervention; Knowledge; Length of Stay; Life; Measures; Memory B-Lymphocyte; Methods; National Institute of Diabetes and Digestive and Kidney Diseases; Ohio; Organ failure; Outcome; Pancreatitis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Pilot Projects; Population; Population Heterogeneity; Process; Publishing; Records; Research; Research Institute; Research Personnel; Serum; Severity of illness; Systemic Inflammatory Response Syndrome; T-Cell Activation; TNF gene; TNFRSF1A gene; Testing; Therapeutic Agents; Time; Time trend; United States National Institutes of Health; Universities; Whole Blood; Work; acute pancreatitis; body system; cell type; clinical research site; clinically relevant; cohort; cost; cytokine; design; ethnic diversity; functional disability; high dimensionality; human data; insight; member; monocyte; mosaic; new therapeutic target; novel; pharmacologic; point of care testing; predictive panel; predictive tools; prospective; receptor; resistin; therapeutic target; time of flight mass spectrometry; time use; transcriptome sequencing

PROJECT SUMMARY/Abstract Acute pancreatitis (AP) accounts for over 300,000 admissions in the U.S. with annual costs exceeding $3 billion. Most cases of AP are mild (MAP) with a hospital stay of 3-4 days, but approximately 15% of AP subjects develop severe disease (SAP), defined by presence of persistent organ failure. Up to a third of SAP patients expire from multi-system organ failure after weeks in the intensive care unit. To date, no therapeutic agents have been successful at ameliorating the protracted hospital course of SAP. The National Institute of Diabetes and Digestive and Kidney Diseases workshops identified two critical knowledge gaps as barriers to developing pharmacologic interventions: 1) the establishment of a highly accurate, early prediction tool to identify which subjects will develop SAP during hospitalization; 2) a more in-depth knowledge of SAP mechanistic pathways and immuno-pathogenesis to identify novel therapeutic targets. We propose the MoSAIC Study (iMmune SIgnAtures and ClIniCal outcomes in AP), a prospective multi- center, observational cohort that will address both of these knowledge gaps in SAP. We recently discovered a novel multi-cytokine panel (angiopoetin-2, hepatocyte growth factor, interleukin-8, resistin, and tumor necrosis factor-α receptor-1) that accurately predicts SAP early in the disease process with an accuracy of 0.89 and significantly outperforms existing prediction tools. Aim 1 of this project is to validate the multi-cytokine panel in a large, ethnically diverse AP population across multiple U.S. clinical sites. In preliminary studies, immunologists at the Benaroya Research Institute (BRI) have identified unique immune cell changes such as an increase in monocytes and a decrease of T follicular helper and memory B cells in blood samples of AP patients compared to healthy controls. In Aim 2, the MoSAIC study will extend this work by defining the circulating immune cells that correspond with cytokine signatures in early AP and identifying the immune pathways driving the development of SAP. This will generate the first high-dimensional phenotypic analysis of immune cell types in human AP and provide new insights into its immune mechanisms. MoSAIC investigators have NIH-funded complementary expertise in pancreatitis and immunology. The team is led by well-published pancreatologists at the Ohio State University and immunologists at BRI, supported by a dedicated bioinformatics core at BRI. It also includes three additional academic medical centers with proven track-records of enrolling ethnically diverse populations into prospective AP research trials. Successful completion of the MoSAIC study will have the following impact by: 1) establishing an accurate, early prediction tool for SAP, 2) providing groundbreaking insight into the early immune events of SAP based on robust human data, 3) identifying therapeutic immune targets for further testing, and 4) establishing a U.S. multicenter research platform for launching clinical trials to test immunotherapies in AP.

项目概要/摘要 急性胰腺炎（AP）在美国占超过300，000次入院，每年的费用超过3美元 亿大多数AP病例为轻度（MAP），住院3-4天，但约15%的AP 受试者发生严重疾病（SAP），其定义为存在持续性器官衰竭。高达三分之一的SAP 患者在重症监护室数周后死于多系统器官衰竭。到目前为止，没有治疗 药物已经成功地改善了SAP的长期住院过程。国家研究所 糖尿病、消化和肾脏疾病研讨会确定了两个关键的知识差距， 开发药物干预措施：1）建立高度准确的早期预测工具， 确定哪些受试者将在住院期间发生SAP; 2）更深入地了解SAP 机制途径和免疫发病机制，以确定新的治疗靶点。 我们提出了MoSAIC研究（AP中的免疫信号和Closure Cal结局），一项前瞻性多因素研究， 中心，观察性队列，将解决SAP中的这两个知识差距。我们最近发现 一种新的多细胞因子组合（血管生成素-2、肝细胞生长因子、白细胞介素-8、白细胞介素-8和肿瘤细胞因子）， 坏死因子-α受体-1），准确预测SAP的早期疾病过程的准确性， 0.89并且显著优于现有的预测工具。本项目的目的一是验证多细胞因子 在美国多个临床研究中心的大型、种族多样的AP人群中进行。 在初步研究中，Benaroya研究所（BRI）的免疫学家已经确定了独特的免疫系统。 细胞变化，如单核细胞增加和T滤泡辅助细胞和记忆B细胞减少， AP患者的血液样品与健康对照相比。在目标2中，MoSAIC研究将扩展这项工作 通过定义与早期AP中细胞因子特征相对应的循环免疫细胞， 免疫途径驱动SAP的发展。这将产生第一个高维表型 分析人类AP中的免疫细胞类型，并为其免疫机制提供新的见解。 MoSAIC研究人员在胰腺炎和免疫学方面拥有NIH资助的补充专业知识。的 该团队由俄亥俄州州立大学的胰腺学家和BRI的免疫学家领导， 由BRI专门的生物信息学核心提供支持。它还包括三个额外的学术医疗中心 在前瞻性AP研究试验中招募不同种族人群的记录已经得到证实。 MoSAIC研究的成功完成将产生以下影响：1）建立一个 SAP的准确，早期预测工具，2）提供对早期免疫事件的突破性见解， SAP基于稳健的人类数据，3）鉴定用于进一步测试的治疗性免疫靶标，以及4） 建立一个美国多中心研究平台，用于启动临床试验，以测试AP的免疫疗法。