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.

项目摘要/摘要 急性胰腺炎（AP）在美国占30万以上的入院，年费用超过$ 3 十亿。大多数AP病例是温和的（地图），住院时间为3-4天，但约占AP的15％ 受试者会出现严重疾病（SAP），这是由持续器官衰竭的存在定义的。最多三分之一 在重症监护病房数周后，患者因多系统器官衰竭而到期。迄今为止，没有治疗 代理商已经成功地改善了SAP的旷日持久的医院课程。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知识差距 开发药学干预措施：1）建立高度准确的早期预测工具 确定在住院期间哪些受试者会出现SAP； 2）对SAP的深入了解 机械途径和免疫性病理发生，以鉴定新的治疗靶标。 我们提出了马赛克研究（AP中的免疫特征和临床结果），这是一种前瞻性的多种多样的 中心，观察人群将解决SAP中这两个知识差距。我们最近发现 一个新型的多环素面板（Angiopoetin-2，肝细胞生长因子，白介素-8，抵抗素和肿瘤 坏死因子-α受体-1）在疾病过程的早期准确预测SAP，准确性 0.89并显着优于现有的预测工具。该项目的目的1是验证多创代因子 在美国多个临床场所的大型，种族多样化的AP人群中。 在初步研究中，Benaroya研究所（BRI）的免疫学家确定了独特的免疫 细胞变化，例如单核细胞的增加以及T卵泡辅助器和记忆B细胞的减少 与健康对照组相比，AP患者的血液样本。在AIM 2中，马赛克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并识别 免疫途径推动了SAP的发展。这将产生第一个高维表型 分析人类AP中免疫细胞类型的分析，并为其免疫力学提供新的见解。 马赛克调查人员已经在胰腺炎和免疫学方面拥有NIH资助的完善专业知识。这 团队由俄亥俄州立大学的胰腺学家发行，BRI的免疫学家， 在BRI的专用生物信息学核心的支持下。它还包括另外三个学术医疗中心 有经过验证的赛道记录，将种族多样化的人群纳入了前瞻性AP研究试验。 成功完成马赛克研究将产生以下影响：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开创性见解 基于强大的人类数据的SAP，3）识别用于进一步测试的治疗免疫靶标，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中的免疫疗法。