The broad, long-term objective of this proposal is to study several mouse models of human disease, growth and development with innovative technology to better understand the role of glycolipids and sphingolipids in mental retardation, and to explain mechanisms of therapeutic reversal. The expected outcome of our two major specific aims, is to verify the hypothesis that microdomain regulation of ceramide, sphingosine and sphingosine-1-phosphate (S1P) is achieved by several different mechanisms, that S1P depletion is common to different neuropathological states and sphingoid-mimicking drugs can play an important role in reversing mental retardation Aim 1. We will take advantage of our recent discovery that the deletion of the gene for NSMase 2 in mice reveals a role for glycolipids, ceramide and SM in brain growth and skeletal development through regulation of AktP and the mTor pathway, creating a model for human osteogenesis imperfecta. We will use a second mouse model (ASMase (-/-)) to further show how the two major SMases are co-regulated and the role of lysosomal hydrolases in the regulation of the Cer/S1P ratio. To achieve this goal we will use HPLC/MS/MS lipidomics and take advantage of the ability of sphingolipids to form microdomains to assemble signaling complexes which can be visualized by transfecting cells with GFP-GPI anchored protein constructs.
Aim 2. We will use a drug-based approach and in vivo animal models, expanding on our recent observation that FTY720 (approved for therapy of Multiple Sclerosis) is lipophilic cationic drug and a functional inhibitor of acid sphingomyelinase (FIASMA) with functional consequences for glycolipid, SM, ceramide and S1P metabolism. To better understand S1P regulation and function we will use an in vivo remyelination model (cuprizone-treated mouse) to determine the effects of FTY720 in vivo and the epigenetic effects of S1P on gene transcription through inhibition of histone deacetylases (HDAC 1/2). We will use MS/MS proteomics to identify specific protein acylation patterns under different Cer/S1P ratios and how this relates to remyelination. We will compare these results with the effect of a glucosyltransferase inhibitor drug (EtDoP4/Epiglustat), in which substrate reduction reverses the depletion of Ceramide and S1P in a number of lysosomal storage diseases involving mental retardation as well as AIDs and Parkinsons disease. The impact of this research will be to better understand how sphingolipids work so that combination drug therapies can be used to treat patients in the future.
Glycolipids have been shown to be involved in many human diseases and our research is focused on better understanding of how they work and how their therapeutic effects can be maximized. We will use mouse models of disease to better understand what has gone wrong and how currently available drugs might be used to correct this and how combinations of drugs can become a more effective therapy. Our long-term goal is to make some impact in helping mentally retarded children live more normal lives.
|Testai, Fernando D; Kilkus, John P; Berdyshev, Evgeny et al. (2014) Multiple sphingolipid abnormalities following cerebral microendothelial hypoxia. J Neurochem 131:530-40|
|Dawson, G; Fuller, M; Helmsley, K M et al. (2012) Abnormal gangliosides are localized in lipid rafts in Sanfilippo (MPS3a) mouse brain. Neurochem Res 37:1372-80|
|Qin, Jingdong; Berdyshev, Evgeny; Poirer, Christophe et al. (2012) Neutral sphingomyelinase 2 deficiency increases hyaluronan synthesis by up-regulation of Hyaluronan synthase 2 through decreased ceramide production and activation of Akt. J Biol Chem 287:13620-32|
|Dawson, Glyn; Qin, Jingdong (2011) Gilenya (FTY720) inhibits acid sphingomyelinase by a mechanism similar to tricyclic antidepressants. Biochem Biophys Res Commun 404:321-3|
|Saadat, Laleh; Dupree, Jeffrey L; Kilkus, John et al. (2010) Absence of oligodendroglial glucosylceramide synthesis does not result in CNS myelin abnormalities or alter the dysmyelinating phenotype of CGT-deficient mice. Glia 58:391-8|
|Dawson, Glyn; Schroeder, Christina; Dawson, Philip E (2010) Palmitoyl:protein thioesterase (PPT1) inhibitors can act as pharmacological chaperones in infantile Batten disease. Biochem Biophys Res Commun 395:66-9|
|Qin, Jingdong; Berdyshev, Evgeny; Goya, Jonathan et al. (2010) Neurons and oligodendrocytes recycle sphingosine 1-phosphate to ceramide: significance for apoptosis and multiple sclerosis. J Biol Chem 285:14134-43|
|Qin, Jingdong; Testai, Fernando D; Dawson, Sylvia et al. (2009) Oxidized phosphatidylcholine formation and action in oligodendrocytes. J Neurochem 110:1388-99|
|Kilkus, John P; Goswami, Rajendra; Dawson, Sylvia A et al. (2008) Differential regulation of sphingomyelin synthesis and catabolism in oligodendrocytes and neurons. J Neurochem 106:1745-57|
|Qin, Jingdong; Goswami, Rajendra; Dawson, Sylvia et al. (2008) Expression of the receptor for advanced glycation end products in oligodendrocytes in response to oxidative stress. J Neurosci Res 86:2414-22|
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