Early detection of colorectal cancer in the traditional and serrated pathways

项目摘要/摘要 结直肠癌(CRC)是全球癌症相关死亡的主要原因。传统型 白光照明的结肠镜检查经常漏掉癌前病变，这些病变要么是平的，要么是微妙的。 外表。在所有已知的病例中，95%的结直肠癌起源于传统途径或锯齿状途径。 这两条途径表达的成像生物标志物的发展可以改进早期结直肠癌的诊断方法 侦测。成功完成目标将导致有针对性的成像战略的概念验证 提高结肠镜检查对结直肠癌早期诊断的有效性。 将优化cMET和过氧化还蛋白-1的特异性多肽单体，并将其排列在异源二聚体中 配置。这些分子靶点在癌前病变中过度表达，这些病变源于 分别是传统路径和锯齿状路径。IRDye800将被用作近红外荧光标签。 使用已知的已知基因，将在体外与细胞和人体结肠标本进行特异性结合验证 抗体。 将开发一种柔性纤维内窥镜附件，以在体内对异源二聚体进行成像。可扩展的 光学设计以大角度扫描小数值孔径光束，以达到衍射极限分辨率 在宽广的视野中。将开发一种基于混合参数共振的微型扫描仪 刚度软化动力学以使梁以大角度偏转。紧凑的外形使 通过标准医用内窥镜活检通道向前传递的仪器。 患者衍生的有机化合物将用于验证多肽异二聚体的特异性结合，并验证 活体柔性纤维内窥镜。这些结肠瘤将从传统的无柄腺瘤发展而来。 锯齿状腺瘤和正常粘膜，并将被原位植入免疫低下的小鼠体内。 这些癌前病变在内窥镜下表现为扁平而细微的特征。目标表达水平和 遗传异质性是临床上常见的癌前病变的代表。 这项合作工作将由多肽开发和验证专家Pi TD Wang领导。 以显像剂为基础。KR Oldham是基于微系统的扫描技术方面的权威，而JR 斯宾塞是开发人类原代器官培养的专家。

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.