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.

摘要 在美国，非酒精性脂肪肝（NAFLD）的患病率估计>25%，使 它是慢性肝病最常见的原因。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，预计到2020年将翻一番。 2030.目前，对于NAFLD还没有有效的药物疗法，但是有许多治疗方法。 有希望的候选药物正在临床试验中进行评估。然而，主要终点 这些试验（组织学纤维化）存在缺陷，包括抽样误差和使用 主观五类量表量化连续变量。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。结合尖端的机器学习技术，我们 假设3D OTLS显微镜可以提供更准确和一致评估 在NASH患者的肝活检中发现了纤维化。我们将通过开发一个 多重染色协议和机器学习分析管道，将于20日进行试点 存档的FFPE肝活检。我们的检测结果将与目前使用的 主要和次要结局指标，以激励进一步的研究与星存档 来自临床试验的响应性和结果数据样本。