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

• 批准号: 10471944
• 负责人: Thomas D Wang
• 金额: $ 33.83万
• 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/10471944
• 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

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.

项目总结/摘要 结直肠癌（CRC）是全球癌症相关死亡的主要原因。常规 使用白色光照明的结肠镜检查经常错过癌前病变， 外观.在>95%的所有已知病例中，CRC由传统途径或锯齿状途径引起。 在这两种途径中表达的成像生物标志物的发展可以改善早期CRC的方法 侦测目标的成功完成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发现CRC的有效性。 对cMet和过氧化物氧还蛋白-1特异的肽单体将被优化并排列在异二聚体中 配置.这些分子靶点在癌前病变中过度表达， 传统的和锯齿状的路径。IRDye 800将用作近红外荧光标记。 特异性结合将使用已知的方法在体外用细胞和离体人结肠标本进行验证。 抗体的 将开发一种柔性纤维内窥镜附件，以在体内成像异二聚体。可缩放 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 在广阔的视野中。基于混合参数共振原理，研制了一种微型扫描仪 刚度软化动力学使梁大角度偏转。紧凑的外形使 该内窥镜可使器械向前通过标准医用内窥镜的活检通道。 患者源性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。 这些癌前病变在内窥镜下表现为扁平和细微的特征。目标表达水平和 遗传异质性是临床上观察到的癌前病变的代表。 这项合作工作将由PI TD Wang领导，他是肽开发和验证专家， 基于造影剂。KR奥尔德姆是基于微系统的扫描技术的权威， Spence是原代人类类器官培养的专家。