Molecular Mechanisms of Heritable Disorders of Lipid Metabolism

Child Health And Human Development

Investigators

Linked publications, trials & patents

Abstract

During the past year we have accomplished the following : (i) by generating two different animal models (i.e. antisense- transgenic and gene-knockout), expressing a low level or lacking uteroglobin, a potent phospholipase A2 (PLA2) inhibitor, we uncovered that both models develop IgA nephropathy, the most common primary renal glomerular disease in the world. We determined the molecular mechanism by which lack of UG causes IgA deposition in the glomeruli of these animals and demonstrated that supplementation of recombinant UG prevents glomerular IgA deposition. Studies in progress will delineate whether the human disease is caused by UG deficiency; (ii) characterized a high-affinity receptor of uteroglobin and its inducible expression in various normal and tumor cell lines. We also found that via this receptor uteroglobin regulates the motility and ECM-invasiveness of many cell types. We also uncovered that via this receptor- mediated pathway uteroglobin may reverse the transformed phenotype of cancer cells expressing the receptor, and in this respect, it manifests a tumor-suppressor-like function; (iii) isolated and characterized mouse palmitoyl-protein thioesterase (mPPT) cDNA and the gene, respectively, and deciphered a temporal pattern suggesting that the expression of this gene in the retina precedes that in the developing brain, explaining in part, why the loss of vision occurs earlier than the deterioration of brain function in infantile neuronal ceroid lipofuscinosis (INCL); (iv) cloned and characterized the cDNA and the gene encoding murine and human palmitoyl-protein thioesterases (PPT, respectively, mutations in which causes infantile ceroid lipofuscinosis (INCL). INCL belongs to a relatively common (1/12,500) autosomal recessive heritable disorder without effective treatment; (v) the gene encoding human acid ceramidase, the mutation of which causes an autosomal recessive heritable disorder of lipid metabolism, Farber lipogranulomatosis, has been cloned and characterized. A corresponding murine cDNA and the gene have also been cloned and attempts being made to generate a mouse model for this disease in order to understand the pathology and to develop an effective treatment; (vi) characterized a high-affinity cell surface receptor for group I phospholipase A2 (PLA2) and found that via this receptor sPLA2-I induces cellular invasion of the extracellular matrix and this receptor is expressed at a high level in several tumor cell lines; (vii) demonstrated a critical role of nuclear factor IL6 (NF IL-6) in the induction of sPLA2-I receptor-mediated activation of the cyclooxygenase- 2 (COX-2) gene expression in MC-3T3 and human colorectal adenocarcinoma cell lines; (viii) cloned and characterized a cDNA and the gene for murine group I pancreatic PLA2 and its differential tissue-specific expression in the mouse; (ix) discovered that sPLA2-I gene expression is drastically down- regulated in colorectal cancer tissues and in the colon of Min (multiple intestinal neoplasia) mouse, an animal model for familial adenomatous polyposis (FAP) and heritable colorectal cancer in humans suggesting a modifier role of sPLA2-I in this disease; (x)) in collaboration with Claragen, Inc., animal studies are performed to determine the tissue distribution and toxicity of recombinant UG towards phase-I clinical trial of this protein in the treatment of inflammatory and fibrotic lung disorders. Patent applications for the use of recombinant UG as a potential therapeutic agent for IgA-nephropathy has been filed. - Infantile Neuronal Ceroid Lipofuscinosis, Batten Disease,IgA-Nephropathy, Farber disease