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.

Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2001
Total Cost
Indirect Cost
Name
U.S. National Inst/Child Hlth/Human Dev
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Mukherjee, Anil B; Zhang, Zhongjian; Chilton, Beverly S (2007) Uteroglobin: a steroid-inducible immunomodulatory protein that founded the Secretoglobin superfamily. Endocr Rev 28:707-25
Zhang, Zhongjian; Lee, Yi-Ching; Kim, Sung-Jo et al. (2007) Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration. Hum Mol Genet 16:837-47
Zhang, Zhongjian; Lee, Yi-Ching; Kim, Sung-Jo et al. (2006) Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL. Hum Mol Genet 15:337-46
Kim, Sung-Jo; Zhang, Zhongjian; Hitomi, Emiko et al. (2006) Endoplasmic reticulum stress-induced caspase-4 activation mediates apoptosis and neurodegeneration in INCL. Hum Mol Genet 15:1826-34
Eisenstein, Eli M; Choi, Moonsuk (2006) Analysis of a uteroglobin gene polymorphism in childhood Henoch-Schonlein purpura. Pediatr Nephrol 21:782-4
Zhang, Zhongjian; Kim, Sung-Jo; Chowdhury, Bhabadeb et al. (2006) Interaction of uteroglobin with lipocalin-1 receptor suppresses cancer cell motility and invasion. Gene 369:66-71
Lee, Yi-Ching; Zhang, Zhongjian; Mukherjee, Anil B (2006) Mice lacking uteroglobin are highly susceptible to developing pulmonary fibrosis. FEBS Lett 580:4515-20
Kim, Sung-Jo; Zhang, Zhongjian; Lee, Yi-Ching et al. (2006) Palmitoyl-protein thioesterase-1 deficiency leads to the activation of caspase-9 and contributes to rapid neurodegeneration in INCL. Hum Mol Genet 15:1580-6
Ray, Rabindranath; Zhang, Zhongjian; Lee, Yi-Ching et al. (2006) Uteroglobin suppresses allergen-induced TH2 differentiation by down-regulating the expression of serum amyloid A and SOCS-3 genes. FEBS Lett 580:6022-6
Ray, Rabindranath; Choi, Moonsuk; Zhang, Zhongjian et al. (2005) Uteroglobin suppresses SCCA gene expression associated with allergic asthma. J Biol Chem 280:9761-4

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