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：
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
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/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

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.

项目摘要/摘要大肠癌（CRC）是全球与癌症相关死亡的主要原因。传统的带有白光照明的结肠镜检查经常会错过平坦或微妙的恶性病变外貌。在所有已知病例中，CRC来自传统或锯齿状的途径。在这两种途径中表达的成像生物标志物的开发可以改善早期CRC的方法检测。成功完成目标将导致目标成像策略的概念证明提高结肠镜检查早期CRC检测的有效性。针对CMET和CMIRDOXIN-1特异的肽单体将优化并在异二聚体中排列配置。这些分子靶标的过度表达，这是由源于机场的病变。传统和锯齿状的途径。 IRDYE800将用作近红外荧光标签。特异性结合将使用已知的体外和人类结肠样品在体外和人类结肠标本中验证抗体。将开发灵活的纤维内窥镜附件来对异二聚体进行映像。可扩展光学设计在大角度上扫描低数值孔径，以实现衍射限制分辨率在广泛的视野上。将根据参数共振而开发微型扫描仪僵化的动力学，以大角度偏转光束。紧凑的外形允许仪器将通过标准医疗内窥镜的活检通道传递。患者衍生的类器官将用于验证肽异二聚体特异性结合并验证体内柔性纤维内窥镜。这些结肠化将从传统的腺瘤，无梗开发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。这些预防性病变具有扁平和微妙的特征。目标表达水平和遗传异质性代表了诊所中观察到的恶性病变。这项合作工作将由Pi Td Wang领导，Pi Td Wang是肽开发和验证的专家 - 基于成像剂。 KR Oldham是基于微系统的扫描技术的权威，JR Spence是主要人体器官培养的专家。