Immune Signatures and Clinical Outcomes in Acute Pancreatitis

急性胰腺炎的免疫特征和临床结果

基本信息

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
项目类别：
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

项目摘要

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/摘要美国有超过 30 万人因急性胰腺炎 (AP) 入院，每年费用超过 3 美元大多数 AP 病例为轻度 (MAP)，住院时间为 3-4 天，但约 15% 的 AP 病例为轻度 (MAP)。受试者出现严重疾病（SAP），其定义是存在持续性器官衰竭，最多有三分之一的 SAP。患者在重症监护病房几周后因多系统器官衰竭而死亡。迄今为止，尚无治疗方法。代理已成功改善 SAP 的长期医院病程。糖尿病和消化及肾脏疾病研讨会确定了两个关键的知识差距作为障碍制定药物干预措施：1）建立高度准确的早期预测工具确定哪些受试者在住院期间会发生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 MoSAIC 研究（AP 中的免疫特征和临床结果），这是一项前瞻性的多因素研究我们最近发现，该中心的观察队列将解决 SAP 中的这两个知识差距。新型多细胞因子组合（血管生成素-2、肝细胞生长因子、白细胞介素-8、抵抗素和肿瘤坏死因子-α 受体-1）可在疾病过程早期准确预测 SAP，准确度为 0.89，并且显着优于现有的预测工具。该项目的目标 1 是验证多细胞因子。在美国多个临床中心的大量、种族多样的 AP 人群中进行了小组调查。在初步研究中，贝纳罗亚研究所 (BRI) 的免疫学家发现了独特的免疫细胞变化，例如单核细胞增加以及滤泡辅助 T 细胞和记忆 B 细胞减少在目标 2 中，MoSAIC 研究将扩展 AP 患者的血液样本与健康对照的血液样本。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并识别驱动 SAP 发展的免疫途径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 研究人员拥有 NIH 资助的胰腺炎和免疫学方面的补充专业知识。该团队由俄亥俄州立大学的著名胰腺学家和 BRI 的免疫学家领导，由 BRI 专门的生物信息学核心提供支持，它还包括另外三个学术医疗中心。拥有将不同种族人群纳入前瞻性 AP 研究试验的良好记录。成功完成 MoSAIC 研究将产生以下影响： 1) 建立 SAP 的准确早期预测工具，2) 提供对 SAP 早期免疫事件的突破性见解 SAP 基于可靠的人体数据，3) 确定治疗性免疫靶点以进行进一步测试，以及 4) 建立美国多中心研究平台，开展 AP 免疫疗法的临床试验。