ANALYSIS OF INTRAHEPATIC MACROPHAGE PROFILES FOR PREDICTING RISK OF FIBROSIS DEVELOPMENT IN PATIENTS WITH DIFFERENT TYPES OF CHRONIC LIVER DISEASE

分析肝内巨噬细胞谱以预测不同类型慢性肝病患者纤维化发展的风险

• 批准号: 10598475
• 负责人: HEATHER L STEVENSON
• 金额: $ 54.88万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598475
• 关键词: Acids; Advanced Development; Alcoholic Liver Diseases; Alcohols; Anti-Inflammatory Agents; Antigens; Archives; Autoimmune Hepatitis; Bioinformatics; Biological Markers; Biological Models; Biopsy; Blood; CCL2 gene; CCR5 gene; Cells; Chronic Hepatitis; Cirrhosis; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Complement; Data; Data Analyses; Development; Diagnosis; Discontinuous Capillary; Disease; Economic Burden; Endothelial Cells; Etiology; Exhibits; Eye; Fibrosis; Formalin; Future; Galectin 3; Gatekeeping; Gene Expression; Genes; Health; Hepatic; Hepatitis C virus; Human; Image; Immunotherapy; In Situ; In Vitro; Inflammatory; Injury; Kupffer Cells; Life Style Modification; Liver; Liver Fibrosis; Liver diseases; Location; Longitudinal Studies; Macrophage; Malignant Neoplasms; Mediator; Molecular; Outcome; Paraffin Embedding; Pathogenicity; Patients; Perisinusoidal Space; Phase; Phenotype; Population; Predisposition; Primary carcinoma of the liver cells; Prior Therapy; Process; Progressive Disease; Pruritus; Recommendation; Slide; Techniques; Technology; Testing; Therapeutic Intervention; Time; Tissue Embedding; Tissue Stains; Tissues; Transforming Growth Factor beta; Tumor Necrosis Factor-Beta; Variant; biobank; chronic liver disease; clinical care; clinical implementation; cost; cost efficient; design; follow-up; improved; innovation; intrahepatic; liver biopsy; liver injury; microscopic imaging; mouse model; nano-string; non-alcoholic fatty liver disease; non-compliance; nonalcoholic steatohepatitis; patient variability; personalized medicine; prognostic; prospective; recruit; response; risk prediction; side effect; spectrograph; standard of care; stellate cell; targeted treatment; therapeutic candidate; therapeutic target

PROJECT SUMMARY/ABSTRACT Cirrhosis and hepatocellular carcinoma are increasing health and economic burdens. Non-alcoholic fatty liver disease (NAFLD/NASH), alcohol-associated liver disease (AALD), chronic hepatitis (CHC), and autoimmune hepatitis (AIH) are common etiologies. Unfortunately, many patients do not adhere to recommended life style modifications, thus, we need better techniques for predicting risk of fibrosis progression and personalizing therapies prior to development of poor outcomes. Intrahepatic macrophages (Macs), liver sinusoidal endothelial cells (LSECs), and stellate cells (HSCs) can greatly influence the composition of the hepatic microenvironment and development of fibrosis. Therapies targeting these initiators of fibrosis are being investigated in phase II-III clinical trials; however, the underlying hepatic microenvironment and patient variability in these cells and expression of these targets is not being considered prior to treatment. We use cutting-edge spectral imaging microscopy combined with NanoString technology to evaluate these cells and associated pro-fibrotic gene expression profiles in the same patient's liver biopsy at the time of initial diagnosis. From our liver tissue biobank, we identified 225 biopsies with different chronic liver diseases (NASH, AALD, CHC, and AIH) that were collected at the time of diagnosis from patients that had adequate follow-up either with a repeat biopsy or by liver replacement (for those that later developed cirrhosis). The majority showed no progression of hepatic fibrosis over time (n = 150) while a portion rapidly developed cirrhosis (n = 75). We use the above platforms to assess differences in these patients' hepatic microenvironments in their initial liver biopsies. We propose to test the hypothesis that patients with definable pro-fibrotic variations in their hepatic microenvironment early in the course of disease predicts their propensity to develop fibrosis. Preliminary data showed that initial liver biopsies from patients with a predisposition to rapidly develop cirrhosis have increased profibrotic macrophages (e.g., Mac387+ and CD163+, respectively), enhanced cellular interactions of Mac-LSEC-HSCs, increased expression of therapy-related targets (e.g., CCR2 and galectin 3) and increased pro-inflammatory/pro-fibrotic gene expression profiles (e.g., CCL2, TNF, and TGF-beta). Imaging and molecular bioinformatics will be used for data analyses. For Aim 1, we will use three panels to phenotype intrahepatic Macs and examine their interactions with LSECs and HSCs, and will assess differences in expression of pro-fibrotic therapy-related targets. For Aim 2, we will analyze over 200 Mac-LSEC-HSC-related and pro-fibrotic genes in the other half of the biopsy from Aim 1. The proposed approach will lay the groundwork for our long-term objective: personalization of targeted therapies (e.g., cenicriviroc or obeticholic acid), similar to the manner in which the response to immunotherapy is predicted by staining of tissue in patients with cancer. In this retrospective longitudinal study, we will determine which platform (Spectral imaging-Aim1 vs. NanoString-Aim 2) is the most performant for determining potential targets of fibrosis progression and most cost efficient for clinical implementation in the future.

项目概要/摘要 肝硬化和肝细胞癌正在增加健康和经济负担。非酒精性脂肪肝 疾病（NAFLD/NASH）、酒精相关性肝病（AALD）、慢性肝炎（CHC）和自身免疫性疾病 肝炎（AIH）是常见病因。不幸的是，许多患者没有遵守推荐的生活方式 因此，我们需要更好的技术来预测纤维化进展的风险和个性化 在出现不良结果之前进行治疗。肝内巨噬细胞 (Macs)、肝窦内皮细胞 细胞（LSEC）和星状细胞（HSC）可以极大地影响肝脏微环境的组成 和纤维化的发展。针对这些纤维化引发剂的疗法正在 II-III 期研究中 临床试验；然而，这些细胞的潜在肝脏微环境和患者变异性 治疗前不考虑这些靶标的表达。我们使用尖端的光谱成像 显微镜结合 NanoString 技术来评估这些细胞和相关的促纤维化基因 初次诊断时同一患者肝活检中的表达谱。从我们的肝组织生物库中， 我们收集了 225 份患有不同慢性肝病（NASH、AALD、CHC 和 AIH）的活检样本 在通过重复活检或肝脏进行充分随访的患者诊断时 替代（对于后来发展为肝硬化的人）。大多数没有表现出肝纤维化进展 随着时间的推移（n = 150），而一部分迅速发展为肝硬化（n = 75）。我们利用以上平台进行评估 这些患者最初肝活检中肝脏微环境的差异。我们建议测试 假设患者的肝脏微环境在病程早期就存在明显的促纤维化变化 疾病的发生预测了他们发生纤维化的倾向。初步数据显示，最初的肝活检 具有快速发展为肝硬化倾向的患者促纤维化巨噬细胞增加（例如， 分别为 Mac387+ 和 CD163+），Mac-LSEC-HSC 的细胞相互作用增强，表达增加 治疗相关靶点（例如 CCR2 和半乳糖凝集素 3）的增加以及促炎/促纤维化基因的增加 表达谱（例如 CCL2、TNF 和 TGF-β）。成像和分子生物信息学将用于数据 分析。对于目标 1，我们将使用三个面板对肝内 Mac 进行表型分析并检查它们的相互作用 与 LSEC 和 HSC 一起使用，并将评估促纤维化治疗相关靶标表达的差异。为了目标 2，我们将分析另一半活检中的 200 多个 Mac-LSEC-HSC 相关基因和促纤维化基因 目标 1. 所提出的方法将为我们的长期目标奠定基础：目标个性化 疗法（例如西尼昔韦罗或奥贝胆酸），类似于免疫疗法的反应方式 通过对癌症患者的组织进行染色来预测。在这项回顾性纵向研究中，我们将确定 哪个平台（光谱成像-Aim1 与 NanoString-Aim 2）在确定潜力方面性能最佳 纤维化进展的目标以及未来临床实施最具成本效益的目标。