Abstract

: Hematopoietic stem cells (HSC) play a central role in the production of all hematopoietic lineages. HSC are functionally defined as having two important characteristics: self-renewal and the capacity to differentiate into all mature hematopoietic lineages. These two characteristics are in sharp contrast to those of mature cells that have limited proliferation and differentiation potential and lack self-renewal properties. In order to maintain a functional hematopoietic system, a population of HSC must be able to regenerate the entire hematopoietic repertoire on a regular basis. Whereas HSC are readily evaluated by transplantation in mice, analysis in humans is quite difficult. Progress in the characterization of HSC has relied, for the most part, on in vitro assays such clonogenic assays (CFCs) and of long-term cultures (LTC-IC). Interest in HSC is widespread because of their many possible clinical applications including transplantation, purging of tumor cells, and gene therapy. Recently, the use of xenografts has facilitated the analysis of the HSC. These models are based on the fact that human hematopoietic cells from fetal liver, bone marrow, umbilical core or peripheral blood (after mobilization) can repopulate the bone marrow of severe combined immune deficient (SCID) mice. In this competitive renewal application in which the investigators propose to use two different but complementary xenograft models to evaluate the in vivo repopulating potential and the suitability for gene transfer of HSC from HIV infected individuals. Since ultimately this is the only source available for cells of future gene therapy protocols.
The specific aims of this proposal are: 1) To determine the quantitative in vivo repopulating potential of hematopoietic stem cells from HIV-1 infected individuals; 2) To determine the in vivo lymphopoietic capacity of T-cell progenitors from HIV-1 individuals; and 3) To characterize the primitive hematopoietic stem cell compartment in HIV-1 infected individuals.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082055-08
Application #
7221212
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (11))
Program Officer
Howcroft, Thomas K
Project Start
2000-05-05
Project End
2009-03-30
Budget Start
2007-04-01
Budget End
2009-03-30
Support Year
8
Fiscal Year
2007
Total Cost
$422,527
Indirect Cost

  Institution

Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390

  Publications

Wege, A K; Melkus, M W; Denton, P W et al. (2008) Functional and phenotypic characterization of the humanized BLT mouse model. Curr Top Microbiol Immunol 324:149-65
Denton, Paul W; Estes, Jacob D; Sun, Zhifeng et al. (2008) Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice. PLoS Med 5:e16
Sun, Zhifeng; Denton, Paul W; Estes, Jacob D et al. (2007) Intrarectal transmission, systemic infection, and CD4+ T cell depletion in humanized mice infected with HIV-1. J Exp Med 204:705-14
Melkus, Michael W; Estes, Jacob D; Padgett-Thomas, Angela et al. (2006) Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med 12:1316-22
Cravens, Petra D; Melkus, Michael W; Padgett-Thomas, Angela et al. (2005) Development and activation of human dendritic cells in vivo in a xenograft model of human hematopoiesis. Stem Cells 23:264-78
Islas-Ohlmayer, Miguel; Padgett-Thomas, Angela; Domiati-Saad, Rana et al. (2004) Experimental infection of NOD/SCID mice reconstituted with human CD34+ cells with Epstein-Barr virus. J Virol 78:13891-900
Gatlin, Joel; Melkus, Michael W; Padgett, Angela et al. (2003) In vivo fluorescent labeling of corneal wound healing fibroblasts. Exp Eye Res 76:361-71
Gatlin, J; Unett, D J; Lerner, M R et al. (2001) Efficient, long-term transgene expression in Xenopus laevis dermal melanophores. Pigment Cell Res 14:275-82
Gatlin, J; Melkus, M W; Padgett, A et al. (2001) Engraftment of NOD/SCID mice with human CD34(+) cells transduced by concentrated oncoretroviral vector particles pseudotyped with the feline endogenous retrovirus (RD114) envelope protein. J Virol 75:9995-9
Gatlin, J; Padgett, A; Melkus, M W et al. (2001) Long-term engraftment of nonobese diabetic/severe combined immunodeficient mice with human CD34+ cells transduced by a self-inactivating human immunodeficiency virus type 1 vector. Hum Gene Ther 12:1079-89

Showing the most recent 10 out of 13 publications