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

用于人类干细胞治疗的新型 NSG 小鼠模型的开发和验证

基本信息

批准号：
8666892
负责人：
Michael Allen Brehm
金额：
$ 78.04万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8666892
关键词：
Address Amyotrophic Lateral Sclerosis Animal Disease Models Animal Model Animals Biomedical Research Cell Therapy Cell model Cells Chimera organism Clinic Clinical Communities Data Development Disease Engraftment Evaluation Experimental Models Gene Expression Goals Hematopoietic Hepatic Human Inbred NOD Mice Institutes Lymphoid Mesenchymal Stem Cells Methods Modeling Mus Muscle satellite cell Muscular Dystrophies Neurons Outcome Physiological Pluripotent Stem Cells Population Regenerative Medicine Research Resources Rodent Rodent Model Safety Stem cell transplant Stem cells Study models Testing The Jackson Laboratory Tissues Translating Treatment Efficacy United States National Institutes of Health Validation base cell type cost effective efficacy evaluation gene therapy human disease human stem cells immunodeficient mouse model in vivo innovation insight interest meetings mouse model new technology novel pre-clinical public health relevance repository stem stem cell biology stem cell population stem cell therapy

项目摘要

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.

描述（由申请人提供）：干细胞疗法正在迅速进入诊所，但是对于人体干细胞的体内分析以评估其功效和安全性，仍然需要有效的实验模型。尽管啮齿动物模型为疾病机制提供了基本见解，但小鼠和人类在细胞组成，功能和基因表达方面有所不同。我们建议使用满足NIH多家机构的紧急需求的新型人性化小鼠模型来解决这个特定物种的问题。我们的新型人性化小鼠模型基于我们的NOD-SCID IL2RGNULL（NSG）和NOD-RAGLNULL IL2RGNULL（NRG）菌株的创建，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疗效。我们的初步数据介绍了新型人性化小鼠模型的开发，这些模型支持植入人类造血，淋巴样和肝干细胞，并且我们正在开发研究模型，用于研究人类神经元干细胞，以治疗肌萎缩性侧向硬化症和肌肉干细胞，以治疗肌肉性疾病。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类干细胞群体植入并提高其治疗功效的能力的基础机制。在这个多学科的多学科团队建议中，我们提出了三个目标：1）生成新的免疫缺陷小鼠模型，用于对人类干细胞的体内评估功能； 2）通过确定人类干细胞在体内产生功能分化的人类细胞和组织的能力来验证模型，以改善疾病，并且； 3）利用杰克逊实验室的全球分销资源使这些新的人源化老鼠模型迅速可供科学界使用。我们的建议利用了强大的新技术来创建新型人性化老鼠的新模型，并以我们20年的近20年往绩来建立生成，验证和共享新颖的人源性小鼠模型的记录。这些模型由我们的多学科团队开发和验证，将迅速分发给科学界，独特地将我们定位为实现此RFA的目标。