During the passed year we have accomplished the following: (i) developed animal models of IgA-nephropathy (IgAN)in mice deficient of uteroglobin (UG), a multifunctional cytokine-like protein.These animals were generated by gene-targeting and by the expression of UG-antisense RNA in transgenic mice. We have also delineated the molecular mechanism(s) by which the lack of UG leads toIgA, fibronectin (Fn) and collagen deposition in the renal glomeruli of these animals. Furthermore, we demonstrated that supplementation of recombinant UG prevents IgAN. Studies in progress will delineate whether the human disease is caused by UG deficiency; (ii) we continued our efferts to isolate and characterize the UG receptor-cDNA and the gene and delineate the signal transduction pathways; (iii) we have characterized the murine pancreatic phospholipase A2 (sPLA2IB) cDNA and the gene, mapped its chromosomal location, determined a novel receptor-mediated function of sPLA2IB in which it regulates the expression of key enzymes involved in the metabolism of both phospholipids and sphingolipids; (iv) we have disrupted palmitoyl-protein thioesterase (PPT) gene in embryonic stem (ES) cells in order to generate an animal model for infantile neuronal ceroid lipofuscinosis (INCL), a heritable, progressive encephalopathy in children for which there is no effective treatment. This disease is caused by inactivating mutations in the PPT gene and is uniformly fatal disorder; (v)we have discovered a novel approach towards a pharmacological treatment of INCL for which a """"""""bench-to-bedside"""""""" clinical protocol has been approved and Cystagon treatment in one patient has already been started; (vi) we characterized the Farber disease gene and delineated novel mutations in patients with this disease; (vii)we have isolated and characterized the murine cDNA and the gene encoding neutral ceramidase (NC); this enzyme has been implicated in many vital cellular processes such as signal transduction and apoptosis and cancer; targeted-disruption of this gene is now being planned; (viii)in a collaborative study we have demonstrated an essential role of osteopontin in murine mammary gland differentiation and lactation; (ix)in CRADA with Claragen, Inc., a phase I clinical trial of recombinant human UG has been initiated to determine the efficasy of this protein in the treatment of inflammatory and fibrotic lung disorders in neonates. A US Patent for the use of recombinant human UG as a potential therapeutic agent for inflammatory and fibrotic disorders has been granted on July 3, 2001.
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