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.
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