Assessing biomarkers of intestinal fibrosis and inflammation in Crohn's Disease via an endoscopic imaging catheter

通过内窥镜成像导管评估克罗恩病肠道纤维化和炎症的生物标志物

• 批准号: 10033948
• 负责人: Peter D.R. Higgins
• 金额: $ 53.08万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10033948
• 关键词: Acute; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Balloon Dilatation; Biological Markers; Biopsy; Catheters; Chronic; Clinical; Clinical Management; Collagen; Colonoscopes; Complement; Crohn' s disease; Diagnostic; Diagnostic Imaging; Diagnostic Procedure; Digestive System Disorders; Disease; Endoscopic Biopsy; Endoscopy; Excision; Extracellular Matrix; Fibrosis; Future; Gastroenterology; Genes; Hemoglobin; Histopathology; Human; Hyperplasia; Hypertrophy; Image; Imaging Techniques; Imaging technology; Inflammation; Inflammatory; Intestinal Diseases; Intestinal Fibrosis; Intestinal Obstruction; Intestines; Length; Magnetic Resonance Imaging; Measurement; Mechanics; Modality; Modeling; Molecular; Monitor; Morphology; Mucous Membrane; Multivariate Analysis; Muscle; Myofibroblast; Operative Surgical Procedures; Optics; Oryctolagus cuniculus; Outcomes Research; Pathologic; Pathology; Patient-Focused Outcomes; Patients; Performance; Phenotype; Pilot Projects; Procedures; Prognostic Marker; Publishing; Research; Resected; Sampling; Sensitivity and Specificity; Signal Transduction; Small Intestines; Stenosis; Techniques; Technology; Testing; Time; Tissue Sample; Tissues; Translations; Ultrasonic Transducer; Ultrasonography; United States; X-Ray Computed Tomography; absorption; accurate diagnosis; base; chronic autoimmune disease; clinical translation; clinically relevant; elastography; experimental study; human subject; human tissue; imaging approach; imaging biomarker; imaging modality; improved; in vivo; in vivo Model; inflammatory disease of the intestine; innovation; instrument; molecular marker; molecular pathology; novel; personalized therapeutic; photoacoustic imaging; pressure; prognostic; success; tool

ABSTRACT Crohn’s disease (CD) produces chronic intestinal bowel damage and stenosis in the majority of patients. Accurate characterization of these strictures is critical, as acute inflammatory strictures can respond to anti- inflammatory therapy, but chronic strictures, which include both fibrosis and muscular hypertrophy, require surgical resection. Intestinal fibrosis is an important predictor of future intestinal obstruction and penetrating complications of CD. The standard diagnostic procedure for CD is endoscopic biopsy, in which small pieces of tissue are removed from the innermost layer of the intestine for histopathology. Due to limited sampling depth, endoscopic biopsy does not assess fibrosis in submucosal and muscular layers. Conventional non-invasive modalities, such as MRI, CT and ultrasound (US), have shown limited sensitivity for intestinal fibrosis. Intestinal strictures are often a mixture of chronic fibrosis and acute inflammation, which are respectively correlated with increased collagen and hemoglobin in tissues, which act as molecular markers of distinct CD pathologies. In addition, extensive previous studies of compressional US elastography have documented that increased stiffness is a mechanical marker of chronic fibrotic strictures. These molecular and mechanical markers complement each other, providing orthogonal diagnostic information. A diagnostic imaging procedure that can simultaneously assess these phenotypes of CD is highly desirable for personalized therapeutic planning and improved patient outcomes. Our preliminary studies in animals in vivo, human tissue samples ex vivo, and in human subjects have validated that the molecular and mechanical markers of CD stricture pathology can be characterized by advanced photoacoustic (PA)-US dual modality imaging approaches, including spectroscopic PA imaging, US elastography, and our recent innovation of strain-PA imaging. An imaging catheter probe compatible with standard ileocolonoscopy procedures, integrating all these imaging technologies, has been developed and validated with tissue samples and in animals in vivo. Encouraged by our exciting preliminary results, we propose to fill this long-standing prognostic gap with accurate characterization of molecular and mechanical phenotypes of CD. In the proposed project, we will first objectively assess the sensitivity and specificity of each molecular and mechanical marker quantified by the proposed imaging technology through experiments on clinically relevant rabbit models. In addition, to pave the road to clinical translation, we will examine the feasibility and identify the limitations of the proposed technique for use during clinical ileocolonoscopy via a pilot study in CD patients. The success of this project will advance these molecular and mechanical biomarkers of distinct pathologies in CD strictures to practical clinical measurement with PA-US dual modality endoscopic imaging, enabling accurate prognostic assessment and treatment monitoring in CD.

抽象的 克罗恩病（CD）在大多数患者中会产生慢性肠道肠损伤和狭窄。 这些狭窄的准确表征至关重要，因为急性炎症狭窄可以响应抗 - 炎症疗法，但慢性狭窄，包括纤维化和肌肉肥大，需要 手术切除。肠纤维化是未来肠反应和穿透性的重要预测指标 CD并发症。 CD的标准诊断程序是内窥镜活检，其中一小部分 从肠的最内向层去除组织以进行组织病理学。由于采样深度有限， 内窥镜活检未评估粘膜下层和肌肉层的纤维化。常规的非侵入性 MRI，CT和超声（US）等模态对肠纤维化的敏感性有限。 狭窄通常是慢性纤维化和急性炎症的混合物，分别与 组织中胶原蛋白和血红蛋白的增加，它们充当不同CD病理的分子标记。在 此外，关于压缩的大量研究美国弹性图已经记录了增加 刚度是慢性纤维化狭窄的机械标记。这些分子和机械标记 相互补充，提供正交诊断信息。可以 同样，评估CD的这些表型对于个性化治疗计划和 改善患者的预后。 我们在体内动物，人体组织样本和人类受试者中的初步研究 证实了CD狭窄病理学的分子和机械标记可以通过 高级光声（PA） - US双态成像方法，包括光谱PA成像，美国 弹性图，以及我们最近对应变-PA成像的创新。成像导管探针与 已经开发了所有这些成像技术的标准回肠造影镜检查，并 用组织样品和体内动物进行验证。 在我们激动人心的初步结果的鼓励下，我们建议用 CD的分子和机械表型的准确表征。在拟议的项目中，我们将首先 客观地评估每个分子和机械标记的灵敏度和特异性 通过对临床相关兔模型的实验提出的成像技术。此外，要铺平 通往临床翻译的道路，我们将检查可行性并确定所提出的技术的局限性 通过在CD患者中进行的试点研究期间使用临床回肠肠道镜检查。该项目的成功将进步 CD狭窄的不同病理学的这些分子和机械生物标志物与实用临床 使用PA-US双重模态内窥镜成像进行测量，实现准确的预后评估和 CD中的治疗监测。