We have:(a) uncovered a novel physiological role of uteroglobin (UG) in preventing severe glomerular inflammatory disease by gene targeting in mice; (b) characterized the entire human UG gene and discovered a polymorphism in Best's disease patients and their family members; (c) discovered that tumor cells, originating from organs which normally express UG gene, do not produce UG and induced overexpression of UG gene in these cells dramatically alters their tumorigenic phenotype in that they fail to have anchorage-independent growth on soft agar (a marker for transformation and tumorigenesis) and have low tumorigenic potential in nude mice, raising the possibility that UG may have tumor-suppressor role; (d) delineated the crystallographic structure of recombinant human UG (hUG) at 1.8 angstroms resolution; (e) resolved the solution structure of recombinant hUG by multidimensional NMR and CD; the results suggest that this protein is nearly identical to rabbit UG; (f) characterized a novel high-affinity cell surface receptor of UG via which UG regulates ECM-invasion in several cell types. (g) established that group I PLA2 via its high-affinity receptor induces ECM-invasion in normal cells. Interestingly, these receptors are overexpressed in several tumor cells; (h) discovered that a mouse model which expresses osteopontin (OPN) antisense mRNA at high level in the mammary gland manifests abnormality in mammary gland development and differentiation; (i) designed and constructed OPN targeting vector transfection of which in ES cells resulted in heterozygotic cells for targeted disruption of OPN gene; these cells will be used to generate OPN knockout mice; (j) demonstrated by using an in vitro assay system that cells lacking proto-oncogene c-fos fail to express OPN gene; since OPN is required for normal osteoclast attachment to the osteoid, a process essential for bone remodeling, our results, at least in part, explains why c-fos-/- mice would develop osteopetrosis and (k) established that high level expression of OPN gene in human coronary artery smooth muscle cells play a critical role in cellular migration, ECM-invasion and proliferation, essential for coronary restenosis after angioplasty, a frequently used procedure for the treatment of coronary atherosclerotic disease.
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