Endoscopic Theranostics System

描述（申请人提供）：每年有超过100万的患者被新诊断为消化系统疾病，如炎症性肠病和结直肠癌。消化道可直接通过内窥镜进行诊断和治疗。然而，目前的成像技术不能提供足够的分辨率和对比度，并且由于缺乏足够的图像引导系统，细胞和组织特异性治疗方法受到阻碍。本项目的主要挑战是开发一种内窥镜光学图像引导的固定细胞治疗系统，该系统可以在显微镜水平上无创地对消化道疾病进行体内诊断，同时进行组织特异性和细胞特异性的生物治疗。如果胃肠道干细胞可供使用，该系统也将用于在消化道内准确地重建它们。该项目是多学科团队在胃肠道病理学、细胞工程和影像学方面的密切合作。第一个具体目标是开发一种基于光学频域成像（OFDI）和共聚焦荧光显微镜的新型高分辨率内窥镜成像系统。该系统将被优化为在细胞水平上对小鼠结肠进行全面成像。第二个目标是开发细胞特异性和组织特异性的消化道疾病生物治疗系统。产前成纤维细胞将被改造成分泌细胞特异性治疗细胞因子，表达造影剂，如细胞特异性绿色荧光蛋白，并采用自杀基因系统来控制组织中治疗细胞因子的表达。我们相信，这个为期2年的项目的影响是非常高的，因为它将开发新的成像技术来改善体内诊断，设计出一种有效的固定细胞系，可以控制治疗和成像造影剂的分泌，并测试内镜图像引导下固定细胞（可能是干细胞）递送治疗结肠直肠肿瘤发生相关肠道炎症的可行性。

DESCRIPTION (provided by applicant): Over one million patients each year are newly diagnosed with digestive diseases, such as inflammatory bowel diseases and colorectal cancer. Digestive tracts are directly accessible by endoscopy for the diagnosis and therapy. However, current imaging techniques do not provide sufficient resolution and contrast, and cell- and tissue-specific therapeutic approaches have been hampered by the lack of adequate image-guided systems. The major challenge of this project is to develop an endoscopic optical image- guided immobile-cell therapy system that can non-invasively make an in vivo diagnosis of digestive tract diseases at the microscopic level and can simultaneously perform the tissue-specific and cell-specific biological therapy. In the event that gastrointestinal stem cells are available for use, this system will also be utilized to accurately reconstitute them within the digestive tract. This project is a close collaboration between multidisciplinary teams with expertise in gastrointestinal pathology, cell engineering, and imaging. The first specific aim is to develop a novel high-resolution endomicroscopy imaging system based on optical frequency-domain imaging (OFDI) and confocal fluorescence microscopy. The system will be optimized for comprehensive imaging of the mouse colon at the cellular level. The second specific aim is to develop cell- specific and tissue-specific biological therapy system for digestive tract diseases. Prenatal fibroblast cells will be engineered to secrete cell-specific therapeutic cytokines, to express contrast agents such as cell- specific green fluorescence proteins, and to employ a suicide gene system for controlling the expression of therapeutic cytokines in the tissue. We believe that the impact of this 2-year project is significantly high, as it will have developed novel imaging techniques for the improved in vivo diagnosis, engineered an effective immobile cell line with controllable secretion of therapeutic and imaging-contrast agents, and tested the feasibility of endoscopic image-guided delivery of immobile cells (potentially stem cells) to treat intestinal inflammation associated with colorectal tumorigenesis. PUBLIC HEALTH RELEVANCE: This challenge grant is designed to develop a novel endoscopy system that can make a histological grade diagnosis of digestive tract diseases through the machine's eye and can simultaneously perform a tissue- specific and cell-specific biological treatment. We believe that the study proposed would provide not only important intervention to develop a novel therapy system for improving the lives of patients with digestive diseases but also a useful tool to further advance the basic and clinical research in the fields of mucosal biology and some digestive diseases.