3D quantification of NASH-related liver fibrosis using open-top light-sheet microscopy

使用开顶光片显微镜对 NASH 相关肝纤维化进行 3D 定量

• 批准号: 10325461
• 负责人: Nicholas Reder
• 金额: $ 26.94万
• 依托单位: ALPENGLOW BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325461
• 关键词: 3-Dimensional; Affect; Aftercare; Archives; Biological Assay; Biopsy; CLIA certified; Categories; Cell Nucleus; Cirrhosis; Clinical; Clinical Data; Clinical Trials; Collagen; Complex; Computer software; Custom; Cytoplasm; Data; Data Set; Detection; Diagnostic; Diagnostic radiologic examination; Disease Outcome; Esters; Evaluation; Failure; Fibrosis; Formalin; Future; Gold; Histologic; Human; Image; Imaging Techniques; Light; Liver; Liver Fibrosis; Machine Learning; Magnetic Resonance Imaging; Malignant neoplasm of prostate; Manuals; Methods; Microscope; Microscopy; Outcome; Outcome Measure; Pathologic; Pathology; Patients; Pharmacotherapy; Phase; Population; Positioning Attribute; Preparation; Prevalence; Primary carcinoma of the liver cells; Process; Protocols documentation; Readiness; Research; Sampling; Sampling Errors; Services; Sirius Red F3B; Small Business Innovation Research Grant; Stains; Techniques; Technology; Testing; Therapeutic Agents; Three-Dimensional Imaging; Three-dimensional analysis; Tissues; Training; Translating; Trichrome stain; United States; Universities; Washington; Work; algorithm training; analysis pipeline; antifibrotic treatment; chronic liver disease; drug candidate; drug efficacy; elastography; high risk; human tissue; improved; lightspeed; liver biopsy; machine learning algorithm; mortality; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; primary endpoint; primary outcome; sample archive; secondary outcome; three dimensional structure; three-dimensional visualization

Abstract Non-alcoholic fatty liver disease (NAFLD) prevalence is estimated at >25% in the U.S., making it the most common cause of chronic liver disease. Non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD, affects 1-3% of the U.S. population and is expected to double by 2030. Currently, there is no effective pharmacotherapy for NAFLD, but there are numerous promising drug candidates being evaluated in clinical trials. However, the primary endpoint for these trials, histologic fibrosis, has shortcomings including sampling error and use of a subjective five category scale to quantify a continuous variable. Our team has pioneered the use of 3D open-top light-sheet (OTLS) microscopy, which enables rapid, high-throughput imaging of large clinical samples. In combination with cutting-edge machine learning techniques, we hypothesize that 3D OTLS microscopy can provide more accurate and consistent assessment of fibrosis in liver biopsies from NASH patients. We will test this hypothesis by developing a multiplex staining protocol and machine learning analysis pipeline, which will be piloted on 20 archived FFPE liver biopsies. Results from our assay will be correlated with currently used primary and secondary outcome measures to motivate further studies with sing archived samples from clinical trials with responsivity and outcomes data.

抽象的 据估计，美国非酒精性脂肪肝 (NAFLD) 患病率>25%，这使得 它是慢性肝病的最常见原因。非酒精性脂肪性肝炎 (NASH) NAFLD 的进展形式，影响 1-3% 的美国人口，预计将增加一倍 2030. 目前，NAFLD尚无有效的药物治疗方法，但有多种治疗方法 有前景的候选药物正在临床试验中进行评估。然而，主要终点 这些组织学纤维化试验存在缺陷，包括抽样误差和使用 主观五类量表来量化连续变量。我们的团队率先使用 3D 开顶光片 (OTLS) 显微镜，可实现快速、高通量成像 大量临床样本。结合前沿的机器学习技术，我们 假设 3D OTLS 显微镜可以提供更准确和一致的评估 NASH 患者肝活检中纤维化的影响。我们将通过开发一个 多重染色方案和机器学习分析流程将于 20 日试行 存档的 FFPE 肝活检。我们的检测结果将与当前使用的相关 用于激励进一步研究的主要和次要结果指标，并存档 来自临床试验的样本以及反应性和结果数据。