The Section on Developmental Genetics conducts both basic and clinical investigations to understand molecular mechanisms of hereditary neurodegenerative and inflammatory/autoimmune diseases and to develop novel approaches for the treatment of these diseases. During the past year we have: (A) uncovered a novel innate homeostatic mechanism that counteracts airway inflammation and protects against allergic asthma. In this scenario, uteroglobin (UG) is an essential component that counteracts inadvertent activation of allergen-induced inflammatory response in this vital organ and prevents allergic asthma; (B) demonstrated that uteroglobin-deficient mice exhibit an altered pulmonary eosinophilic inflammation. Our results provided the first in vivo evidence that UG plays a role in the modulation of pulmonary allergic inflammation; (C) delineated the molecular mechanism of inhibition of phospholipase A2 activity by UG. By site-specific mutation, we demonstrated that Lys 43 Glu, Asp 46 Lys or a combination of the two mutations in the full-length, recombinant human UG (rhUG) abrogates its sPLA2-inhibitory activity; (D) under a collaborative research and development agreement (CRADA) a Phase I clinical study of recombinant human UG for prevention of bronchopulmonary dysplasia in premature infants with respiratory distress syndrome was successfully completed. Clinical development of rhUG for prevention of neonatal BPD with a Phase II trial, as well as continuing the pre-clinical work for the application of rhUG in ARDS and asthma will be carried out in the coming year; (E) initiated pilot study to determine whether Cystagon is beneficial for infantile neuronal ceroid lipofuscinosis (INCL) patients.This study will continue until we recruit 5 patients, as approved and final analyses will be made when all data are available. Publications: Chowdhury B, Mantile-Selvaggi G, Miele L, Cordella-Miele E, Zhang Z, Mukherjee AB. Lys 43 and Asp 46 in alpha-helix 3 of uteroglobin are essential for its phospholipase A2 inhibitory activity. Biochem Biophys Res Commun. 2002, 295(4):877-83; Wang CY, Lei HJ, Huang CY, Zhang Z, Mukherjee AB, Yuan CJ. Induction of cyclooxygenase-2 by staurosporine through the activation of nuclear factor for IL-6 (NF-IL6) and activator protein 2 (AP2) in an osteoblast-like cell line. Biochem Pharmacol. 2002 Jul 15;64(2):177-84; Mandal AK, Zhang Z, Chou JY, Mukherjee AB. Pancreatic phospholipase A2 via its receptor regulates expression of key enzymes of phospholipid and sphingolipid metabolism. FASEB J. 2001 Aug;15(10):1834-6. No abstract available. Mandal AK, Zhang Z, Chou JY, Zimonjic D, Keck CL, Popescu N, Mukherjee AB. Molecular characterization of murine pancreatic phospholipase A(2). DNA Cell Biol. 2001 Mar;20(3):149-57; Zhang Z, Butler JD, Levin SW, Wisniewski KE, Brooks SS, Mukherjee AB. Lysosomal ceroid depletion by drugs: therapeutic implications for a hereditary neurodegenerative disease of childhood. Nat Med. 2001 Apr;7(4):478-84. Momeda K, Zhang Z, Mukherjee AB, Dhanireddy R. A novel in situ method of SV40 transfection for the establishment of immortal pulmonary alveolartype II cell lines. Ann N Y Acad Sci. 2000;923:325-31. Chowdhury B, Mantile-Selvaggi G, Kundu GC, Miele L, Cordella-Miele E, Zhang Z, Mukherjee AB. Amino acid residues in alpha-helix-3 of human uteroglobin are critical for its phospholipase A2 inhibitory activity. Ann N Y Acad Sci. 2000;923:307-11. Review. No abstract available. Choi M, Zhang Z, Ten Kate LP, Collee JM, Gerritsen J, Mukherjee AB. Human uteroglobin gene polymorphisms and genetic susceptibility to asthma. Ann N Y Acad Sci. 2000;923:303-6. No abstract available. Kundu GC, Zhang Z, Mantile-Selvaggi G, Mandal A, Yuan CJ, Mukherjee AB. Uteroglobin binding proteins: regulation of cellular motility and invasion in normal and cancer cells. Ann N Y Acad Sci. 2000;923:234-48. Zhang Z, Kundu GC, Zheng F, Yuan CJ, Lee E, Westphal H, Ward J, DeMayo F, Mukherjee AB. Insight into the physiological function(s) of uteroglobin by gene-knockout and antisense-transgenic approaches. Ann N Y Acad Sci. 2000;923:210-33. Review. Pattabiraman N, Matthews JH, Ward KB, Mantile-Selvaggi G, Miele L, Mukherjee AB. Crystal structure analysis of recombinant human uteroglobin and molecular modeling of ligand binding. Ann N Y Acad Sci. 2000;923:113-27. Zhang Z, Mandal AK, Mital A, Popescu N, Zimonjic D, Moser A, Moser H, Mukherjee AB. Human acid ceramidase gene: novel mutations in Farber disease. Mol Genet Metab. 2000 Aug;70(4):301-9. Yuan CJ, Mandal AK, Zhang Z, Mukherjee AB. Transcriptional regulation of cyclooxygenase-2 gene expression: novel effects of nonsteroidal anti-inflammatory drugs. Cancer Res. 2000 Feb 15;60(4):1084-91. Zheng F, Kundu G, Zhang Z, Mukherjee AB, Ward J, DeMayo F. Identical glomerulopathy in two different mouse models of uteroglobin deficiency. Am J Kidney Dis. 2000 Feb;35(2):362-3. Mantile G, Fuchs C, Cordella-Miele E, Peri A, Mukherjee AB, Miele L Stable, long-term bacterial production of soluble, dimeric, disulfide-bonded protein pharmaceuticals without antibiotic selection. Biotechnol Prog. 2000 Jan-Feb;16(1):17-25 Nemir M, Bhattacharyya D, Li X, Singh K, Mukherjee AB, Mukherjee BB. Targeted inhibition of osteopontin expression in the mammary gland causes abnormal morphogenesis and lactation deficiency. J Biol Chem. 2000 Jan 14;275(2):969-76.
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