Abstract

It has been hypothesized that some hematologic abnormalities in AIDS patients could be caused by disruption of stem/progenitor cell function as the result of dysregulated stromal cell supporting functions following their infection with HIV-1. Alternatively, it has been hypothesized that these abnormalities could be the result of viral products, T cell/macrophage cytokines, or direct viral infection of stem/progenitor cells. HIV-1-induced pathologic changes in stromal cells and stem/progenitor cells will be modeled by two different, but complementary means: (i) by long-term culture (LTC) and high proliferative potential colony forming cell (HPP-CFC) system; and (ii) by using a novel small animal model created by engrafting human stromal cells and CD34+ cells in neonatal SCID (hu-nSCID) mice. The specific goals of this proposed study are: (i) to determine whether the cellular tropic and cytopathic characteristics of distinct HIV-1 isolates effects the ability of stromal cells to provide support for """"""""long-term culture initiating cells"""""""" (LTC-IC) of bone marrow; (ii) to investigate whether the cellular tropic and cytopathic characteristics of distinct HIV-1 isolates allows for infection and death of hematopoietic stem/progenitor cells; and (iii) to utilize human CD34/stromal cell-engrafted SCID mice to study HIV-1 infection.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK049886-02
Application #
2150842
Study Section
Special Emphasis Panel (ZHL1-CSR-C (S1))
Project Start
1994-09-30
Project End
1998-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Tschan, M P; Reddy, V A; Ress, A et al. (2008) PU.1 binding to the p53 family of tumor suppressors impairs their transcriptional activity. Oncogene 27:3489-93
Tschan, M P; Gullberg, U; Shan, D et al. (2008) The hDMP1 tumor suppressor is a new WT1 target in myeloid leukemias. Leukemia 22:1087-90
Tschan, Mario P; Fischer, Kimberlee M; Fung, Vivian S et al. (2003) Alternative splicing of the human cyclin D-binding Myb-like protein (hDMP1) yields a truncated protein isoform that alters macrophage differentiation patterns. J Biol Chem 278:42750-60
Manchester, Marianne; Smith, Kent A; Eto, Danelle S et al. (2002) Targeting and hematopoietic suppression of human CD34+ cells by measles virus. J Virol 76:6636-42
Buhler, B; Lin, Y C; Morris, G et al. (2001) Viral evolution in response to the broad-based retroviral protease inhibitor TL-3. J Virol 75:9502-8
Anderson, K L; Nelson, S L; Perkin, H B et al. (2001) PU.1 is a lineage-specific regulator of tyrosine phosphatase CD45. J Biol Chem 276:7637-42
Anderson, K L; Perkin, H; Surh, C D et al. (2000) Transcription factor PU.1 is necessary for development of thymic and myeloid progenitor-derived dendritic cells. J Immunol 164:1855-61
Crisa, L; Cirulli, V; Smith, K A et al. (1999) Human cord blood progenitors sustain thymic T-cell development and a novel form of angiogenesis. Blood 94:3928-40
Anderson, K L; Smith, K A; Perkin, H et al. (1999) PU.1 and the granulocyte- and macrophage colony-stimulating factor receptors play distinct roles in late-stage myeloid cell differentiation. Blood 94:2310-8
Miyoshi, H; Smith, K A; Mosier, D E et al. (1999) Transduction of human CD34+ cells that mediate long-term engraftment of NOD/SCID mice by HIV vectors. Science 283:682-6

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