Improved large animal model for the study of adult stem cells

描述（由申请人提供）：尽管使用鼠模型在多能成体干细胞的研究中取得了进展，但由于鼠和人生理学和疾病状态的差异，仍存在显著的翻译限制。例如，在最近的一次肠干细胞联盟会议上，由NIDDK和NIAID建立的团队科学倡议，确定缺乏大型动物模型系统是将肠干细胞研究从实验室转化为床边的最紧迫障碍之一。修复几乎所有胃肠道损伤原因的基本机制是由成体干细胞增殖驱动的结构和功能重建。了解成人干细胞在急性或慢性损伤后再生阶段的行为是基础科学家和临床医生的强烈兴趣，并为发现基于干细胞的疗法以及可以促进重建和修复的新型药理学药物和移植方法提供了平台。该提案的目标是设计转基因猪，使成年干细胞，其祖细胞和干细胞生态位本身的研究成为可能，使用大型动物模型，具有解剖学，生理学和再现人类疾病的能力，克服了啮齿动物模型的现有局限性。成功完成所提出的目标将产生一个强大的动物模型，用于研究肠道，皮肤，肝脏和肾脏等成体干细胞的翻译方面。该猪模型将用于回答关于干细胞在稳态和肠、肝、肾和皮肤疾病/损伤（包括癌症）以及辐射/化疗或病毒/细菌损伤导致的再生反应期间上皮替代中的作用的问题。我们的方法是独特的，因为我们建议标记皮肤，肠，肝，肾和推定的癌症干细胞标志物和关键的利基支持生长因子，使我们能够更好地了解干细胞和支持细胞之间的关系。所提出的动物模型也将在多器官系统中具有实用性，并且更普遍地在再生医学背景下理解支持细胞和干细胞之间的关系。因此，该提案影响到多个NIH中心。

DESCRIPTION (provided by applicant): Although advances in the study of multipotent adult stem cells have been made using murine models, significant translational limitations remain due to differences in murine and human physiology and disease states. For instance, at a recent meeting of the Intestinal Stem Cell Consortium, a team- science initiative established by the NIDDK and NIAID, identified the absence of a large animal model system as one of the most pressing impediments to translation of intestinal stem cell research from bench to bedside. A fundamental mechanism for repair of nearly all causes of gastrointestinal injury is reconstitution of architecture and function, driven by the proliferation of adult stem cells. Understanding the behavior of adult stem cells in the regenerative phase following acute or chronic insult is of intense interest to basic scientists and clinicians and provides a platform for discovery of stem cell-based therapies as well as novel pharmacologic agents and transplantation approaches that can promote reconstitution and repair. The goal of this proposal is to engineer transgenic pigs that will enable the study of adult stem cells, their progenitors and the stem-cell niche per se, using a large animal model having an anatomy, physiology, and ability to recapitulate human disease that overcomes the current limitations of rodent models. Successful completion of the proposed aims will generate a powerful animal model for study of translational aspects of adults stem cells of the gut, skin, liver, and kidney among others. This swine model will be used to answer questions regarding the role of stem cells in epithelial replacement during homeostasis and intestinal, hepatic, renal and skin diseases/injuries, including cancer, and regenerative responses resulting from radiation/chemotherapeutic or viral/ bacterial damage. Our approach is unique in that we propose to label a skin, intestine, liver, kidney and putative cancer stem cell marker and a key niche-supporting growth factor allowing us to better understand the relationship between stem cells and support cells. The proposed animal model will also have utility in multiple organ systems, and more generally in understanding the relationship between support cells and stem cells in a regenerative medicine context. As such this proposal affects multiple NIH centers.