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

描述(申请人提供)：干细胞疗法正在迅速进入临床，但仍然迫切需要有效的实验模型来对人体干细胞进行体内分析，以评估其有效性和安全性。尽管啮齿动物模型提供了对疾病机制的基本见解，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特定物种的问题，这些模型可以满足NIH多个研究所的迫切需求。基于我们创建的NOD-SCID IL2rgnull(NSG)和NOD-RaglullIL2rgnull(NRG)菌株，我们的新型人源化小鼠模型将支持人类干细胞生物学的体内研究，并允许评估人类干细胞治疗疾病的有效性。我们的初步数据描述了新型人源化小鼠模型的开发，这些模型支持植入具有功能的人造血干细胞、淋巴样干细胞和肝脏干细胞，我们正在开发用于治疗肌萎缩侧索硬化症的人类神经干细胞和用于治疗肌营养不良的肌肉干细胞的研究模型。在所有这些模型中，可以研究人类间充质干细胞促进组织特异性人类干细胞群体植入和提高其治疗效果的潜在机制。在这个多PI、多学科的团队提案中，我们提出了三个目标：1)建立新的免疫缺陷小鼠模型，用于体内人类干细胞的功能评估；2)通过确定人类干细胞在体内产生功能性分化的人类细胞和组织以改善疾病的能力来验证模型；以及3)利用杰克逊实验室在世界各地的分布资源，使这些新的人源化小鼠模型迅速提供给科学界。我们的建议利用强大的新技术来创建新的人性化小鼠模型，并建立在我们在生成、验证和共享新型人性化小鼠模型方面20年的跟踪记录的基础上。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，为我们实现RFA的目标提供独特的地位。

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.