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.

项目摘要/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），酒精相关肝病（AALD），慢性肝炎（CHC）和自身免疫性 肝炎（AIH）是常见的病因。不幸的是，许多患者不遵守推荐的生活方式 因此，修改，我们需要更好的技术来预测纤维化进展和个性化的风险 在发展不良预后之前的疗法。肝内巨噬细胞（MAC），肝窦内皮 细胞（LSEC）和星状细胞（HSC）可以极大地影响肝微环境的组成 和纤维化的发展。在II-III期中，正在研究针对这些纤维化启动器的疗法 临床试验；但是，这些细胞的基本肝微环境和患者变异性以及 这些靶标的表达在治疗前不被考虑。我们使用尖端的光谱成像 显微镜与纳米串技术结合以评估这些细胞和相关的纤维化基因 初始诊断时，同一患者的肝活检中的表达谱。来自我们的肝组织生物库， 我们确定了225例患有不同慢性肝病的活检（NASH，AALD，CHC和AIH） 在接受重复活检或肝脏进行足够随访的患者诊断时 替代（对于后来发展的肝硬化的人）。大多数没有显示肝纤维化的进展 随着时间的流逝（n = 150），而一部分迅速发展（n = 75）。我们使用上述平台评估 这些患者的初始肝活检中的肝微环境的差异。我们建议测试 假设在课程初期的肝微环境中具有可定义的促纤维化变异的患者 疾病预测了它们发展纤维化的倾向。初步数据表明，初始肝活检 易于快速发展肝硬化的患者具有纤维化巨噬细胞的增加（例如， MAC387+和CD163+），Mac-LSEC-HSC的细胞相互作用增强，增加了表达 与治疗相关的靶标（例如CCR2和Galectin 3）和促炎/促纤维化基因的增加 表达曲线（例如CCL2，TNF和TGF-BETA）。成像和分子生物信息学将用于数据 分析。对于AIM 1，我们将使用三个面板进行表型内肝内Mac并检查其相互作用 使用LSEC和HSC，并将评估促纤维化治疗相关靶标的表达差异。目的 2，我们将分析来自另一半的活检中的200多个Mac-LSEC-HSC相关和促纤维化基因 目的1。拟议的方法将为我们的长期目标奠定基础：针对性的个性化 疗法（例如，牛尼葡萄酸或obeticholic酸），类似于对免疫疗法的反应方式 通过在癌症患者中组织染色来预测。在这项回顾性纵向研究中，我们将确定 哪个平台（频谱成像-AIM1与纳米串 - AIM 2）是确定潜力的最佳性能 纤维化进展的靶标和未来临床实施的最具成本效益的目标。