Early detection of colorectal cancer in the traditional and serrated pathways

通过传统途径和锯齿状途径早期发现结直肠癌

基本信息

批准号：
10244933
负责人：
Thomas D Wang
金额：
$ 34.52万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/10244933
关键词：
Address Affinity Antibodies Appearance Area Binding Biochemical Biological Biological Assay Biological Markers Biopsy Cancer Etiology Cell surface Cells Cessation of life Clinic Clinical Clinical Research Colon Colonoscopy Colorectal Cancer Community Physician Contrast Media DNA Detection Development Devices Dimensions Disease Early Diagnosis Effectiveness Endoscopes Endoscopy Excision Fecal occult blood Fiber Fluorescence Genetic Heterogeneity Heterogeneity Human Image Imaging Device Immunocompromised Host Implant In Vitro Kinetics Label Lesion Ligands Light Lighting Localized Lesion Malignant Neoplasms Medical Methods MicroRNAs Molecular Molecular Target Mucous Membrane Mus Optics Organ Organoids Pathway interactions Patients Peptides Performance Physicians Pre-Clinical Model Primary Care Physician Procedures Protein Fragment Proteins Resected Resolution Scanning Screening for cancer Serrated Adenoma Specificity Specimen Structure Surface Technology Testing Validation Visualization Work adenoma authority base clinically relevant colon cancer screening colorectal cancer screening contrast imaging design detection sensitivity flexibility fluorescence imaging fluorophore hexanoic acid human subject imaging agent imaging biomarker imaging modality improved in vivo in vivo imaging instrument microsystems minimally invasive monomer overexpression patient population peroxiredoxin I premalignant prevent prototype response routine imaging targeted imaging tumor progression

项目摘要

Project Summary/Abstract Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Conventional colonoscopy with white light illumination frequently misses pre-malignant lesions that are either flat or subtle in appearance. CRC arises from either the traditional or serrated pathways in >95% of all known cases. Development of imaging biomarkers expressed in these two pathways can improve methods for early CRC detection. Successful completion of the aims will result in proof-of-concept for a targeted imaging strategy to improve the effectiveness of colonoscopy for early CRC detection. Peptide monomers specific for cMet and peroxiredoxin-1 will be optimized and arranged in a heterodimer configuration. These molecular targets are over expressed by pre-malignant lesions that arise from the traditional and serrated pathways, respectively. IRDye800 will be used as a near-infrared fluorescence label. Specific binding will be validated with cells in vitro and human colon specimens ex vivo using known antibodies. A flexible fiber endoscope accessory will be developed to image the heterodimer in vivo. The scalable optical design scans a low numerical aperture beam at large angles to achieve diffraction-limited resolution over a wide field-of-view. A miniature scanner will be developed based on parametric resonance with mixed stiffness-softening dynamics to deflect the beam at large angles. The compact form factor allows the instrument to be passed forward through the biopsy channel of standard medical endoscopes. Patient-derived organoids will be used to validate specific binding by the peptide heterodimer and verify the flexible fiber endoscope in vivo. These colonoids will be developed from traditional adenomas, sessile serrated adenomas, and normal mucosa, and will be implanted orthotopically in immunocompromised mice. These pre-malignant lesions appear endoscopically with flat and subtle features. Target expression levels and genetic heterogeneity are representative of pre-malignant lesions seen in the clinic. This collaborative work will be led by PI TD Wang, an expert in development and validation of peptide- based imaging agents. KR Oldham is an authority in microsystems-based scanning technologies, and JR Spence is an expert in development of primary human organoid cultures.

项目概要/摘要结直肠癌（CRC）是全球癌症相关死亡的主要原因。传统的使用白光照明的结肠镜检查经常会漏掉平坦或细微的癌前病变。外貌。在所有已知病例中，超过 95% 的 CRC 都是由传统途径或锯齿状途径引起的。开发这两种途径表达的成像生物标志物可以改进早期 CRC 的方法检测。成功完成这些目标将导致有针对性的成像策略的概念验证提高结肠镜检查早期 CRC 检测的有效性。 cMet 和 peroxiredoxin-1 特异性的肽单体将被优化并排列成异二聚体配置。这些分子靶点在癌前病变中过度表达，这些病变是由分别为传统路径和锯齿状路径。 IRDye800将用作近红外荧光标记。将使用已知的体外细胞和离体人类结肠样本来验证特异性结合抗体。将开发一种柔性纤维内窥镜附件，用于对体内异二聚体进行成像。可扩展性光学设计以大角度扫描低数值孔径光束，以实现衍射极限分辨率广阔的视野。将开发基于参数共振与混合的微型扫描仪刚度软化动力学使梁以大角度偏转。紧凑的外形允许仪器通过标准医用内窥镜的活检通道向前传递。患者来源的类器官将用于验证肽异二聚体的特异性结合并验证体内柔性纤维内窥镜。这些类结肠将从传统的腺瘤、无蒂腺瘤发展而来。锯齿状腺瘤和正常粘膜，并将原位植入免疫功能低下的小鼠体内。这些癌前病变在内窥镜下表现为平坦且微妙的特征。目标表达水平和遗传异质性代表了临床上看到的癌前病变。这项合作工作将由 PI TD Wang 领导，他是肽开发和验证方面的专家。基显像剂。 KR Oldham 是基于微系统的扫描技术领域的权威，而 JR Spence 是原代人类类器官培养开发方面的专家。