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：
8849519
负责人：
Michael Allen Brehm
金额：
$ 74.88万
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/8849519
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 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 nerve stem cell 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，以评估其功效和安全性。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存在差异。我们建议使用新型人源化小鼠模型来解决这一物种特异性问题，以满足 NIH 多个机构的迫切需求。我们基于 NOD-scid IL2rgnull (NSG) 和 NOD-Raglnull IL2rgnull (NRG) 菌株创建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对治疗疾病。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治疗肌萎缩侧索硬化症的人类神经元干细胞和用于治疗肌萎缩侧索硬化症的肌肉干细胞的模型。肌肉营养不良症的治疗。在所有这些模型中，可以研究人类间充质干细胞增强组织特异性人类干细胞群的植入并提高其治疗功效的能力的机制。在这个多PI、多学科团队提案中，我们提出了三个目标：1）生成新的免疫缺陷小鼠模型，用于人类干细胞的功能体内评估； 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； 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。我们的提案利用强大的新技术来创建新的人源化小鼠模型，并建立在我们超过 20 年的生成、验证和共享新的人源化小鼠模型方面的记录基础上。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，为我们实现本 RFA 的目标提供独特的定位。