In Vivo Imaging of Neoplasia

肿瘤的体内成像

• 批准号: 7487616
• 负责人: Brian D. Ross
• 金额: $ 196.12万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-14 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487616
• 关键词: Vivo; Imaging; Neoplasia

DESCRIPTION (provided by applicant): The broad, long-term objectives of this research plan are to develop an integrated optical molecular imaging strategy that uses fluorescence peptides as probes to target the presence of pre-malignant (dysplastic) tissue in viva Macroscopic and microscopic fluorescence instruments are developed as complementary imaging methods for peptide detection. This methodology can be used for monitoring biomarker expression in small animal models and for the early detection of cancer in human patients undergoing screening. In this application, the colonic adenoma is used as a model for dysplasia. The specific aims are to 1) identify 5 candidate peptides using techniques of phage display for biopanning against cultured cells and freshly excised specimens of human colonic mucosa, 2) develop new optical imaging instrumentation using the dual axes confocal architecture to visualize the tissue micro architecture relevant to peptide binding, and 3) validate preferential peptide binding to dysplasia in vivo in a genetically engineered mouse that forms polyps in the distal colon by somatic activation of Cre-recombinase and in human subjects undergoing routine screening colonoscopy. Peptides are chosen for development as probes because their high diversity and small size can provide high affinity binding with deep tissue penetration, and their low risk of immunogenicity and toxicity facilitate translation for use in the clinic. Phage display is a powerful combinatorial technique that provides an unbiased approach for identifying unique peptides that exhibit affinity binding to dysplastic mucosa as is well suited to accommodate subtle changes associated with the in vivo microenvironment. The dual axes confocal architecture provides an instrument that can achieve sub-cellular resolution with long working distance and overcomes the effects of tissue scattering using off-axis fluorescence collection. Moreover, this design can be scaled down in size for endoscope compatibility. A 5 mm diameter instrument package is sufficiently small to pass through a 6 mm diameter instrument channel in a therapeutic endoscope. High speed scanning is performed with a tiny MEMS (micro-electro-mechanical systems) mirror that collects optical sections at a sufficient frame rate for generating 3D volumetric images. The candidate peptides will be topically applied to colonic adenomas and surrounding normal appearing mucosa followed by macroscopic fluorescence imaging to localize regions of increased peptide binding for subsequent microscopic fluorescence imaging to assess the spatial distribution of peptide binding within the dysplastic crypt micro architecture. Public Health: The proposed studies will result in the development of novel optical imaging probes and instruments that can be evaluated in pre-clinical models as well as translated to the clinic as practical screening tool for the early detection of cancer in hollow organs.

描述（由申请人提供）：本研究计划的广泛，长期目标是制定一种综合的光学分子成像策略，该策略使用荧光肽作为探针，以靶向VIVA宏观和微观透镜仪器中的前态（异常）组织的存在作为互补的成像方法开发，以进行隔离剂的检测。该方法可用于监测小动物模型中的生物标志物表达，并在接受筛查的人类患者中早期检测到癌症。在此应用中，结肠腺瘤被用作发育不良的模型。 The specific aims are to 1) identify 5 candidate peptides using techniques of phage display for biopanning against cultured cells and freshly excised specimens of human colonic mucosa, 2) develop new optical imaging instrumentation using the dual axes confocal architecture to visualize the tissue micro architecture relevant to peptide binding, and 3) validate preferential peptide binding to dysplasia in vivo in a genetically engineered通过体细胞激活CRE成年酶和接受常规筛查结肠镜检查的人类受试者，在远端结肠中形成息肉的小鼠。选择肽作为探针进行开发，因为它们的高多样性和小尺寸可以提供高亲和力的结合，并具有深层组织穿透性，并且其免疫原性和毒性的低风险促进了在临床中使用的转化。噬菌体显示是一种强大的组合技术，它提供了一种无偏的方法来识别与异型粘膜相关结合的独特肽，非常适合适应与体内微环境相关的微妙变化。双轴共聚焦体系结构提供了一种可以实现较长工作距离的亚细胞分辨率的仪器，并使用离轴荧光收集来克服组织散射的效果。此外，该设计的尺寸可以缩小，以使内窥镜兼容。直径5毫米的仪表套件足够小，可以通过治疗性内窥镜的直径为6 mm的仪表通道。高速扫描是使用微小的MEMS（微电力系统）镜像进行的，该镜像以足够的帧速率收集光学截面，以生成3D体积图像。候选肽将局部应用于结肠腺瘤和周围的正常出现粘膜，然后进行宏观荧光成像，以定位于增加肽结合的区域，以进行随后的显微镜荧光成像，以评估肽层结合的空间分布在增生性密码微型体系结构中。 公共卫生：拟议的研究将导致可以在临床前模型中评估的新型光学成像探针和仪器的开发，并将其转化为诊所作为空心器官早期检测到癌症的实用筛查工具。