Heritable Autoimmune and Neurodegenerative 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 inflammatory/autoimmune and neurodegenerative diseases and to develop novel approaches for the treatment of these diseases. Towards these goals our studies are focused on understanding the regulation and physiological functions of several genes and their products. These include uteroglobin (UG), soluble phospholipases A2 (sPLA2s), palmitoyl-protein thioesterase (PPT) and neutral ceramidase. UG is a multifunctional secreted protein with potent sPLA2 inhibitory and immunomodulatory activities. By generating UG-deficient mice we demonstrated that these animals suffer from IgA-nephropathy, the most common primary renal glomerular disease for which there is no effective treatment. Thus, one of our goals is to understand the molecular mechanisms of this disease using our animal model and to develop novel therapeutic approaches. While studying the relationship between UG and sPLA2 , we serendipitously isolated another gene encoding palmitoyl-protein thioesterase (PPT) and found that inactivating mutations in this gene leads to infantile neuronal ceroid lipofuscinosis (INCL), the most severe form of childhood Batten disease that has no effective treatment. Currently, we are conducting a pilot study to determine whether Cystagon may be effective treatment for INCL. While the clinical investigations are ongoing, we have returned to the bench to understand the molecular mechanisms of this disease in further detail using a mouse model of INCL and to develop novel therapeutic approaches using gene transfer and embryonic stem (ES) cell technologies. During the past year we have accomplished the following: (a)Novel Role of Uteroglobin as a Repressor of PGD2 Receptor-Mediated COX-2 Gene Expression: Implications for Allergic Asthma; (b)Prostaglandin F2a receptor (FP)-mediated activation of NF-kB and COX-2 gene expression is inhibited by uteroglobin; (c)Uteroglobin-knockout mice are predisposed to lung tumorigenesis when exposed to NNK commonly present in cigarette smoke; (d)In a piglet model of neonatal respiratory distress syndrome, it has been demonstrated intratracheal administration of recombinant uteroglobin (rUG) reduces inflammatory markers and no significant toxicity was noted raising the possibility that rUG may represent a promising therapy for the prevention of lung injury in preterm infants with RDS; (e)Interfeon-g (IFN-g) Stimulates the Expression of a Novel Secretoglobin Gene in Lymphoblasts; (f)cortical degeneration in PPT-KO mice could be determined by MRI paving the way for assessing the outcome of various treatment modalities using this animal model; (g)the preliminary results of the ongoing pilot study to determine if cystagon is beneficial for the treatment of infantile neuronal ceroid lipofuscinosis indicate that some parameters of this disease are stable and/or slightly improved by this treatment; (h)neutral ceramidase is part of a novel homeostatic mechanism to prevent apoptosis in vital organs such as the gastrointestinal tract and the kidneys.