Abstract

The investigation of human hemopoietic stem cells (HSC) has been hindered by the lack of suitable small animal models. We have recently addressed this deficiency by utilizing genetically altered strains of scid mice to develop a small animal model of human hemopoiesis. This model will now be used to determine the role of murine host genes on human HSC engraftment and the in vivo competitive repopulation of different human stem cell populations. To accomplish these goals, we propose an integrated approach involving 2 laboratories with expertise in mammalian genetics and in the development and characterization of small animal models of human cell engraftment.
Specific Aim number 1 will utilize classical mammalian genetics in combination with transgenic and knockout technology to develop improved immunodeficient mouse recipients for human HSC engraftment. We have already shown that the genetic background of the NOD-scid mouse with defects in innate immunity allows a 5-10-fold increase in engraftment of human cord blood cells over that of C.B-17-scid mice. In Preliminary Studies we have documented that NOD-scid-beta2m0/0 mice engraft at higher levels with human stem cells than do NOD-scid mice, and that NOD-rag-10/0 mice engraft with human peripheral blood cells at levels comparable to that of NOD-scid mice. We will improve this model system by generating new transgenic and knockout immunodeficient NOD mice.
Specific Aim number 2 will test these new genetic stocks of mice to identify the optimal host for human HSC engraftment. A novel competitive repopulation assay will be used to quantify the competitive engraftment of two or more human stem cell populations obtained from different individuals simultaneously in a single scid mouse. The development and validation of a small animal model of human hemopoiesis should also allow rapid evaluation and application of advances in gene therapy, and be important for designing treatment for hemopoietic disorders, AIDS, and other diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK057199-03
Application #
6517716
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Badman, David G
Project Start
2000-03-01
Project End
2004-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
3
Fiscal Year
2002
Total Cost
$241,520
Indirect Cost

  Institution

Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655

  Publications

Hosur, Vishnu; Johnson, Kenneth R; Burzenski, Lisa M et al. (2014) Rhbdf2 mutations increase its protein stability and drive EGFR hyperactivation through enhanced secretion of amphiregulin. Proc Natl Acad Sci U S A 111:E2200-9
Hosur, Vishnu; Cox, Melissa L; Burzenski, Lisa M et al. (2013) Retrotransposon insertion in the T-cell acute lymphocytic leukemia 1 (Tal1) gene is associated with severe renal disease and patchy alopecia in Hairpatches (Hpt) mice. PLoS One 8:e53426
Shultz, Leonard D; Lyons, Bonnie L; Burzenski, Lisa M et al. (2005) Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol 174:6477-89
Capillo, Manuela; Mancuso, Patrizia; Gobbi, Alberto et al. (2003) Continuous infusion of endostatin inhibits differentiation, mobilization, and clonogenic potential of endothelial cell progenitors. Clin Cancer Res 9:377-82
Shultz, Leonard D; Banuelos, Scott J; Leif, Jean et al. (2003) Regulation of human short-term repopulating cell (STRC) engraftment in NOD/SCID mice by host CD122+ cells. Exp Hematol 31:551-8
Ohishi, Kohshi; Varnum-Finney, Barbara; Bernstein, Irwin D (2002) Delta-1 enhances marrow and thymus repopulating ability of human CD34(+)CD38(-) cord blood cells. J Clin Invest 110:1165-74
Dell'Agnola, Chiara; Rabascio, Cristina; Mancuso, Patrizia et al. (2002) In vitro and in vivo hematopoietic potential of human stem cells residing in muscle tissue. Exp Hematol 30:905-14
Rossi, M I; Medina, K L; Garrett, K et al. (2001) Relatively normal human lymphopoiesis but rapid turnover of newly formed B cells in transplanted nonobese diabetic/SCID mice. J Immunol 167:3033-42
Ballen, K K; Valinski, H; Greiner, D et al. (2001) Variables to predict engraftment of umbilical cord blood into immunodeficient mice: usefulness of the non-obese diabetic--severe combined immunodeficient assay. Br J Haematol 114:211-8
Joliat, M J; Shultz, L D (2001) The molecular bases of spontaneous immunological mutations in the mouse and their homologous human diseases. Clin Immunol 101:113-29

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