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.
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. The novel models of humanized mice that will be developed in this project 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.
|Borel, Florie; Sun, Huaming; Zieger, Marina et al. (2018) Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema. Proc Natl Acad Sci U S A 115:2788-2793|
|Gawron, Melissa A; Duval, Mark; Carbone, Claudia et al. (2018) Human Anti-HIV-1 gp120 Monoclonal Antibodies with Neutralizing Activity Cloned from Humanized Mice Infected with HIV-1. J Immunol :|
|Verma, Mohit K; Clemens, Julia; Burzenski, Lisa et al. (2017) A novel hemolytic complement-sufficient NSG mouse model supports studies of complement-mediated antitumor activity in vivo. J Immunol Methods 446:47-53|
|Hosur, Vishnu; Low, Benjamin E; Avery, Cindy et al. (2017) Development of Humanized Mice in the Age of Genome Editing. J Cell Biochem 118:3043-3048|
|Walsh, Nicole C; Kenney, Laurie L; Jangalwe, Sonal et al. (2017) Humanized Mouse Models of Clinical Disease. Annu Rev Pathol 12:187-215|
|Gernoux, Gwladys; Wilson, James M; Mueller, Christian (2017) Regulatory and Exhausted T Cell Responses to AAV Capsid. Hum Gene Ther 28:338-349|
|Borel, Florie; Tang, Qiushi; Gernoux, Gwladys et al. (2017) Survival Advantage of Both Human Hepatocyte Xenografts and Genome-Edited Hepatocytes for Treatment of ?-1 Antitrypsin Deficiency. Mol Ther 25:2477-2489|
|Kooreman, Nigel G; de Almeida, Patricia E; Stack, Jonathan P et al. (2017) Alloimmune Responses of Humanized Mice to Human Pluripotent Stem Cell Therapeutics. Cell Rep 20:1978-1990|
|Lee, Jungmin; Dykstra, Brad; Spencer, Joel A et al. (2017) mRNA-mediated glycoengineering ameliorates deficient homing of human stem cell-derived hematopoietic progenitors. J Clin Invest 127:2433-2437|
|Jangalwe, Sonal; Shultz, Leonard D; Mathew, Anuja et al. (2016) Improved B cell development in humanized NOD-scid IL2R?null mice transgenically expressing human stem cell factor, granulocyte-macrophage colony-stimulating factor and interleukin-3. Immun Inflamm Dis 4:427-440|
Showing the most recent 10 out of 21 publications