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）：该研究计划的广泛、长期目标是开发一种集成光学分子成像策略，该策略使用荧光肽作为探针来靶向体内存在的癌前（发育不良）组织的宏观和微观荧光仪器是作为肽检测的补充成像方法而开发的。该方法可用于监测小动物模型中的生物标志物表达以及用于接受筛查的人类患者的癌症早期检测。在本申请中，结肠腺瘤被用作发育异常的模型。具体目标是 1) 使用噬菌体展示技术识别 5 种候选肽，用于针对培养细胞和新鲜切除的人类结肠粘膜样本进行生物淘选，2) 使用双轴共焦架构开发新的光学成像仪器，以可视化相关的组织微架构肽结合，3) 在通过体细胞激活 Cre 重组酶在远端结肠中形成息肉的基因工程小鼠体内以及在经历过常规筛查结肠镜检查。选择肽作为探针进行开发是因为它们的高多样性和小尺寸可以提供高亲和力结合和深层组织渗透，并且它们的免疫原性和毒性风险低，有利于转化用于临床。噬菌体展示是一种强大的组合技术，它提供了一种公正的方法来识别独特的肽，这些肽表现出与发育不良粘膜的亲和力，并且非常适合适应与体内微环境相关的微妙变化。双轴共焦架构提供了一种能够在长工作距离下实现亚细胞分辨率的仪器，并利用离轴荧光收集克服组织散射的影响。此外，该设计可以缩小尺寸以实现内窥镜兼容性。 5 毫米直径的器械包足够小，足以穿过治疗内窥镜中直径 6 毫米的器械通道。使用微型 MEMS（微机电系统）镜进行高速扫描，该镜以足够的帧速率收集光学切片，以生成 3D 体积图像。候选肽将局部应用于结肠腺瘤和周围正常的粘膜，然后进行宏观荧光成像，以定位肽结合增加的区域，以便随后进行显微荧光成像，以评估发育不良的隐窝微结构内肽结合的空间分布。 公共卫生：拟议的研究将导致新型光学成像探针和仪器的开发，这些探针和仪器可以在临床前模型中进行评估，也可以转化为临床，作为早期检测中空器官癌症的实用筛查工具。