Heritable Neurodegenerative and Autoimmune Disorders

Child Health And Human Development

Investigators

Linked publications & trials

Abstract

The Section on Developmental Genetics conducts both basic and clinical investigations to understand molecular mechanisms of heritable neurodegenerative-, and autoimmune disorders in order to develop novel therapeutic approaches. Investigations in this Section are focused primarily on two genes: Uteroglobin (UG) or Clara cell 10kDa (CC10) protein and palmitoyl-protein thioesterase-1 (PPT-1). Uteroglobin (UG), the founding member of the Secretoglobin superfamily, is a multifunctional secreted protein with potent anti-inflammatory and anti-chemotactic properties. Recently, we developed UG-deficient (UG-KO) mice by gene-targeting in embryonic stem (ES) cells. These mice develop 3 major phenotypes: (i) immunoglobulin A nephropathy, worldwide the most common primary glomerular disease for which currently there is no effective treatment; (ii) pulmonary inflammation and focal fibrosis, and (iii) increased susceptibility to carcinogen-induced pulmonary adenomas. Last year, we reported that allergen-sensitization and challenge of UG-KO mice cause exaggerated airway inflammation, reminiscent of allergic asthma. Now, we discovered that in addition to an increased expression of Th2 cytokines, eotaxin and eosinophil infiltration in the lungs,the airway epithelia of these mice also express high levels of cyclooxygenases-2, a critical enzyme for the production of prostaglandins, which are potent lipid mediators of inflammation. Most importantly, these allergen-induced inflammatory responses are abrogated by recombinant UG-treatment raising the possibility that UG is a drug target for allergic asthma. In a related study, we have also characterized a novel Secretoglobin gene and mapped it to chromosome 11q12-13, a region in which the UG gene cluster is localized. Interestingly, we found that the expression of this gene is induced by interferon-g and we named this gene interferon-inducible Secretoglobin or IIS. Since interferon-g manifests antiviral properties, it is likely that IIS may possess similar immunological properties. The second gene studied in this Section encodes palmitoyl-protein thioesterase-1 (PPT1) that facilitates the degradation (recycling) of post-translationally acylated polypeptides by cleaving thioester linkages. Inactivating mutations in this gene causes infantile neuronal ceroid lipofuscinosis (INCL), a heritable, uniformly fatal neurodegenerative disease of childhood. PPT1-deficiency leads to abnormal lysosomal deposition of acylated polypeptides (ceroids) causing INCL pathogenesis. Children afflicted with INCL are normal at birth but become blind by 2 years and brain-dead by age 4. In recent laboratory studies we uncovered that drugs with nucleophilic properties functionally mimic PPT1 and it has the potential to be beneficial to the INCL patients. Based on the results of these studies we are currently conducting a ?bench-to-bedside? study to determine the effectiveness of Cystagon, a nucleophilic drug, as a potential therapeutic for INCL. Simultaneously, we are continuing our efforts to understand the natural history and molecular mechanisms of pathogenesis of INCL in greater detain using a PPT-knockout mouse model of INCL. We are mindful of the fact that evaluation of potential therapeutic approaches would require techniques to assess the effects of new treatment modalities in vivo. Accordingly, using the PPT1-KO mice, we determined that magnetic resonance imaging (MRI) combined with computerized axial tomography (CT) scanning and spectroscopy are excellent means to evaluate neurodegenerative changes in the PPT-KO mice. We hope to develop novel therapeutic approaches to INCL by applying the gene transfer as well as embryonic and neuronal stem (ES) cell technologies. **Publications:1. Choi, M. S., Anderson, M.A., Zhang, Z., Zimonjic, D.B., Popescu, N. and Mukherjee, A.B. Neutral ceramidase gene: Role in regulating ceramide-induced apoptosis. (2003) Gene315:113-122;Chandra, S., Davis, J.M., Drexler, S., Kowalewska, J., Koo, H. C., Chester, D., Pollack, S., Welch, R, Pilon, A. and Levine, C.R. (2003) Pediatr Res. (2003)54:509-515; 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, 295:877-83; 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. 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; 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.Zheng F, Kundu GC, Zhang Z, Ward J, DeMayo F, Mukherjee AB.Uteroglobin is essential in preventing immunoglobulin A nephropathy in mice. Nat Med.5: 1999 1018-25;Loss of transformed phenotype in cancer cells by overexpression of the uteroglobin gene. Proc Natl Acad Sci1999 Mar 30;96(7):3963-8; Zhang Z, Mandal AK, Wang N, Keck CL, Zimonjic DB, Popescu NC, Mukherjee AB. (1999)Palmitoyl-protein thioesterase gene expression in the developing mouse brain and retina: implications for early loss of vision in infantile neuronal ceroid lipofuscinosis.Gene. 231(1-2):203-11.