Development and Validation of Novel NSG Mouse Models for Human Stem Cell Therapy

描述（由申请人提供）：干细胞治疗正在迅速进入临床，但仍然迫切需要用于人体干细胞体内分析的有效实验模型，以评估其疗效和安全性。尽管啮齿动物模型为疾病机制提供了基本的见解，但小鼠和人类在细胞组成，功能和基因表达方面存在差异。我们建议使用新的人源化小鼠模型来解决这个物种特异性问题，以满足NIH多个研究所的迫切需求。我们基于我们创建的NOD-scid IL 2 rgnull（NSG）和NOD-Raglnull IL 2 rgnull（NRG）菌株的人源化小鼠的新模型将支持人干细胞生物学的体内研究，并允许评估人干细胞用于治疗疾病的功效。我们的初步数据描述了新型人源化小鼠模型的开发，该模型支持功能性人类造血干细胞、淋巴干细胞和肝干细胞的植入，并且我们正在开发用于研究人类神经元干细胞治疗肌萎缩侧索硬化症和肌肉干细胞治疗肌营养不良症的模型。在所有这些模型中，可以研究人间充质干细胞增强组织特异性人干细胞群体的植入并增加其治疗功效的能力的潜在机制。在这个多PI，多学科的团队提案中，我们提出了三个目标，将：1）产生用于人体干细胞功能体内评估的免疫缺陷小鼠的新模型; 2）通过确定人体干细胞在体内产生改善疾病的功能分化的人体细胞和组织的能力来验证模型; 3）利用杰克逊实验室的全球分销资源，使这些新的人源化小鼠模型迅速提供给科学界。我们的提案利用了强大的新技术来创建新的人源化小鼠模型，并建立在我们20多年来生成，验证和共享新的人源化小鼠模型的记录基础上。这些由我们的多学科团队开发和验证的模型将迅速分发给科学界，使我们能够实现RFA的目标。

DESCRIPTION (provided by applicant): Stem cell therapy is rapidly advancing into the clinic, but there remains a critical need for effective experimental models for in vivo analyses of human stem cells to evaluate their efficacy and safety. Although rodent models have provided fundamental insights into disease mechanisms, mice and humans differ in terms of cell composition, function, and gene expression. We propose to address this species-specific issue using novel humanized mouse models that meet urgent needs of multiple institutes at NIH. Our novel models of humanized mice based on our creation of NOD-scid IL2rgnull (NSG) and NOD-Raglnull IL2rgnull (NRG) strains will support the in vivo study of human stem cell biology and permit evaluation of the efficacy of human stem cells for the treatment of diseases. Our preliminary data describes development of novel humanized mouse models that support engraftment with functional human hematopoietic, lymphoid, and hepatic stem cells and that we are developing models for the study of human neuronal stem cells for the treatment of amyotrophic lateral sclerosis and muscle stem cells for the treatment of muscular dystrophy. In all of these models, the mechanisms underlying the ability of human mesenchymal stem cells to enhance engraftment of tissue-specific human stem cell populations and increase their therapeutic efficacy can be investigated. In this multi-PI, multi-disciplinary team proposal, we propose three Aims that will: 1) Generate new models of immunodeficient mice for the functional in vivo evaluation of human stem cells; 2) Validate the models by determining the ability of human stem cells to generate functional differentiated human cells and tissues in vivo that ameliorate disease, and; 3) Leverage the world-wide distribution resources of The Jackson Laboratory to make these new humanized mouse models rapidly available to the scientific community. Our proposal takes advantage of powerful new technologies for creating new models of humanized mice, and builds on our >20 year track record for generating, validating, and sharing of novel models of humanized mice. These models developed and validated by our multi-disciplinary team will be rapidly distributed to the scientific community, uniquely positionig us to achieve the goals of this RFA.