Assessment of Alcoholic Hepatitis with Multiparametric Magnetic Resonance Elastography

多参数磁共振弹性成像评估酒精性肝炎

基本信息

批准号：
10205237
负责人：
VIJAY H. SHAH
金额：
$ 38.17万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-22 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10205237
关键词：
Alcoholic Hepatitis Alcoholic Liver Diseases Animal Model Biological Markers Chemical Shift Imaging Cirrhosis Clinic Clinical Clinical Research Clinical Trials Diagnosis Diagnostic Disease Disease Progression Disease regression Enrollment Ethanol Fatty Liver Fibrosis Goals Hepatic Histologic Histology Human IgG2 Image Inflammation Liver Liver Regeneration Liver diseases Longitudinal Studies Magnetic Resonance Elastography Magnetic Resonance Imaging Methods Modeling Monitor Morbidity - disease rate Mus Pathogenesis Patients Phase Placebos Recombinants Research Severities Severity of illness Statistical Models Surrogate Markers Technology Testing Therapeutic Agents base bench to bedside clinical Diagnosis clinical care cohort effective therapy follow-up high risk imaging biomarker innovation interleukin-22 liver biopsy mortality mouse model noninvasive diagnosis novel outcome forecast patient oriented research pre-clinical preclinical study prognostic quantitative imaging recruit response success treatment response treatment trial virtual biopsy

项目摘要

PROJECT SUMMARY/ABSTRACT Alcoholic hepatitis (AH) is a major cause of morbidity and mortality due to a lack of effective treatments. There is an unmet need for reliable noninvasive diagnosis, prognosis, and disease monitoring surrogate markers in AH patients, who often have challenging clinical diagnoses and high risks of complications with invasive liver biopsy. The overall goals of this proposal are to perform both preclinical (phase UH2) and clinical (phase UH3) studies to evaluate multiple magnetic resonance elastography (MRE) biomarkers to assess AH disease severity and monitor treatment responses. Our central hypothesis is that a multiparametric liver MRE, called a hepatogram, can provide accurate parameters for assessing AH disease progression and regression, including changes in steatosis, inflammation, and fibrosis. We believe that AH disease severity and treatment responses can be quantified when the hepatogram is integrated into a composite metric that can serve as a “virtual biopsy,” providing a reliable noninvasive surrogate for assessing AH disease severity. In phase UH2 (years 1-2; Aim 1), we will advance MRE technology to validate the relationships between each imaging parameter and the corresponding histologic feature in mice administered ethanol (EtOH). A statistical model will expand the use of these imaging biomarkers to an all-in-one diagnostic or prognostic score for AH. Recombinant IL-22, an agent that ameliorates hepatic steatosis and inflammation in mouse models will be used to promote disease regression. We will test the ability of MRE in a longitudinal study for assessing AH severity and evaluate changes of each parameter for indicating both disease progression and regression in AH mouse models with placebo or IL-22 treatment. In phase UH3 (years 3-5; Aim 2), we will verify MRE reliability for assessing AH disease severity and treatment responses in patients with AH. Predicated on the upcoming translational patient-oriented studies (RFA AA-18-002 and RFA AA-18-005) in the AlcHepNet at Mayo Clinic, we will perform a baseline MRE in patients who have had liver biopsies as part of their clinical care. We will verify the reliability of each imaging surrogate from MRE for correlation with histology features (steatosis, inflammation, and fibrosis). Additionally, a statistical model of this all-in-one “virtual biopsy” will be verified. We will also perform baseline, 30-, and 90-day follow-up hepatograms in the placebo and IL-22 cohorts from patients enrolled in a Mayo treatment trial of IL-22 (in response to RFA AA-18-005). This will allow us to evaluate MRE parameter changes in AH progression and regression respectively by correlating changes in MRE with changes in Model of End Stage Liver Disease (MELD) scores. In summary, successful verification of this novel MRE based biomarker in the proposed preclinical and clinical studies would have tremendous applications for assessing AH disease severity and response to therapy.

项目概要/摘要由于缺乏有效的治疗方法，酒精性肝炎（AH）是发病和死亡的主要原因。对可靠的无创诊断、预后和疾病监测替代标志物的需求尚未得到满足 AH 患者的临床诊断往往具有挑战性，且侵袭性肝并发症的风险很高该提案的总体目标是进行临床前（UH2 期）和临床（UH3 期）。评估多种磁共振弹性成像 (MRE) 生物标志物以评估 AH 疾病的研究我们的中心假设是多参数肝脏 MRE，称为“多参数肝脏 MRE”。肝图，可以为评估 AH 疾病进展和消退提供准确的参数，包括我们认为脂肪变性、炎症和纤维化的变化与 AH 疾病的严重程度和治疗反应有关。当肝图被整合到一个可以作为“虚拟数据”的综合指标中时，就可以量化活检”，为评估 UH2 阶段（1-2 年；目标1），我们将推进MRE技术来验证每个成像参数与注射乙醇（EtOH）的小鼠的相应组织学特征将扩展统计模型。使用这些成像生物标志物对 AH（一种重组 IL-22）进行一体化诊断或预后评分。改善小鼠模型肝脏脂肪变性和炎症的药物将用于促进疾病我们将在纵向研究中测试 MRE 评估 AH 严重程度的能力。用于指示 AH 小鼠模型中疾病进展和消退的每个参数的变化在 UH3 阶段（第 3-5 年；目标 2），我们将验证 MRE 评估 AH 的可靠性。 AH 患者的疾病严重程度和治疗反应基于即将到来的转化。 Mayo Clinic 的 AlcHepNet 中以患者为导向的研究（RFA AA-18-002 和 RFA AA-18-005），我们将作为临床护理的一部分，对接受过肝活检的患者进行基线 MRE。 MRE 的每个成像替代物与组织学特征（脂肪变性、炎症、此外，我们还将验证这种一体化“虚拟活检”的统计模型。对安慰剂组和 IL-22 组患者进行基线、30 天和 90 天随访肝图检查参加了 Mayo 的 IL-22 治疗试验（响应 RFA AA-18-005），这将使我们能够评估 MRE。通过将 MRE 的变化与终末期肝病模型（MELD）评分的变化综上所述，成功验证了这部小说。基于 MRE 的生物标志物在拟议的临床前和临床研究中将具有巨大的应用评估 AH 疾病的严重程度和对治疗的反应。