The proposed research focuses on determination of mechanism underlying the immunopathological and hematopoietic abnormalities in mice homozygous for the motheaten (me) mutation which causes severe immunodeficiency, systemic autoimmunity, and inflammatory joint disease. This mutation is a null mutation within the hematopoietic cell phosphatase (Hcph) gene. Hcph encodes a cytoplasmic protein-tyrosine phosphatase termed SHP-1. The long-term goal is to understand the role of SHP-1 in regulating the immune and hematopoietic systems in normal and pathologic states. In vitro molecular and biochemical studies have shown the SHP-1 palsy a critical role as a negative regulator in many signaling pathways which regulate the growth and function of lymphoid and myeloid cells. In vivo, SHP-1-deficient me/me mice develop macrophage and granulocyte populations that cause severe inflammation in the lungs, skin, and elsewhere. It is postulated that these abnormal monomyeloid cells interfere with the development, function, or survival of other hematopoietic cell populations including lymphocytes, NK cells, and erythroid cells. To understand the role of SHP-1 in monomyeloid cell development and function, transgenic mice selectively expressing wild-type Hcph in monomyeloid cells were generated. Genetic crosses between these transgenic mice and me/me mice will result in the selective rescue of SHP-1 expression in monomyeloid cells of me/me mice. This will facilitate discrimination between the primary effects of SHP-1 deficiency in other cell populations and secondary effects due to the abnormal monomyeloid cells. It is hypothesized that transgenic cell lineage-specific rescue of SHP-1 in monomyeloid cells will prevent monomyeloid cell-driven inflammatory disease and will reveal primary effects of in vivo SHP-1 deficiency in non-myeloid cell populations.
The specific aims are: I. To evaluate transgenic expression of SHP-1 directed by the lysozyme, CD11b and CD68 promoters; II. To determine the cell types in which SHP-1 must be transgenically rescued to increase longevity in me/me mice; and III. To assess the effects of transgenic rescue of monomyeloid SHP-1 on immunopathologic changes in me/me mice. Determination of the role of SHP-1 deficiency in regulation of monomyeloid cells and of each hematopoietic cell lineage will lead to an understanding of the central function of SHP-1 in the regulation of the immune system in normal and pathologic states.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA020408-25S1
Application #
6346870
Study Section
Immunobiology Study Section (IMB)
Program Officer
Rosenfeld, Bobby
Project Start
1976-12-01
Project End
2002-11-30
Budget Start
2000-12-01
Budget End
2001-11-30
Support Year
25
Fiscal Year
2001
Total Cost
$44,810
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Saito, Yoriko; Uchida, Naoyuki; Tanaka, Satoshi et al. (2010) Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol 28:275-80
Yamamoto, Takashi; Kaizu, Chikako; Kawasaki, Takashi et al. (2008) Macrophage colony-stimulating factor is indispensable for repopulation and differentiation of Kupffer cells but not for splenic red pulp macrophages in osteopetrotic (op/op) mice after macrophage depletion. Cell Tissue Res 332:245-56
Chen, Jian; Wu, Qi; Yang, Pingar et al. (2006) Determination of specific CD4 and CD8 T cell epitopes after AAV2- and AAV8-hF.IX gene therapy. Mol Ther 13:260-9
Huang, Zan; Coleman, John M; Su, Yan et al. (2005) SHP-1 regulates STAT6 phosphorylation and IL-4-mediated function in a cell type-specific manner. Cytokine 29:118-24
Zhang, Huang-Ge; High, Katherine A; Wu, Qi et al. (2005) Genetic analysis of the antibody response to AAV2 and factor IX. Mol Ther 11:866-74
Park, Il-Kyoo; Shultz, Leonard D; Letterio, John J et al. (2005) TGF-beta1 inhibits T-bet induction by IFN-gamma in murine CD4+ T cells through the protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1. J Immunol 175:5666-74
Li, Lina; Hsu, Hui-Chen; Stockard, Cecil R et al. (2004) IL-12 inhibits thymic involution by enhancing IL-7- and IL-2-induced thymocyte proliferation. J Immunol 172:2909-16
Hayashi, Shin-Ichi; Tsuneto, Motokazu; Yamada, Takayuki et al. (2004) Lipopolysaccharide-induced osteoclastogenesis in Src homology 2-domain phosphatase-1-deficient viable motheaten mice. Endocrinology 145:2721-9
Zhang, H-G; Hsu, H-C; Yang, P-A et al. (2004) Identification of multiple genetic loci that regulate adenovirus gene therapy. Gene Ther 11:4-14
Makatsori, Dimitra; Kourmouli, Niki; Polioudaki, Hara et al. (2004) The inner nuclear membrane protein lamin B receptor forms distinct microdomains and links epigenetically marked chromatin to the nuclear envelope. J Biol Chem 279:25567-73

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