The broad, long-term objectives are to understand the role of glycolipids (glycoshingolipids (GSL) and inositolphosphoglycerides) in normal nervous function and the pathogenic processes involving them which lead to mental retardation. To achieve this goal we will use cultured cells which express either neural-specific properties (neurons, neurotumor hybrid cell lines, oligodendrocytes), or inherited metabolic defects (fibroblasts), in conjunction with metabolic studies, enzyme assays, specific antibodies, and cDNA transfection of specific proteins. The two major Specific Aims are: 1) To understand how receptors are coupled to the activation of phospholipase C (PLC) and the hydrolysis of phosphoinositides, and how this system is regulated by protein kinase A, protein kinase C, glycolipids and derived free sphingosine bases. a) We will focus on low molecular weight GTP-binding proteins such as rap1b, their turnover, phosphorylation, membrane association and coupling to receptors and PLC. We will study three cell lines in which receptor-PLC coupling seems to be regulated differently, namely NCB-20, WEHI-3 and human oligodendroglioma cells. b) We will determine how sphingosines activity, and how they could physiologically regulate both PK-C and PLC activity, and how their re- palmitoylation could be related to the acylation/deacylation of bioactive proteins such as GAP-43. 2) To elucidate the role of glycosphingolipids in the mechanism of certain types of neural cell injury. a) We will study hypoxia in neonatal rat oligodendrocytes since hypoxia initially restricts O2 for 2-hydroxy fatty acid GSL synthesis and depletes ATP levels sufficiently to disrupt inter- organellar translocation and phosphorylation of key myelin proteins. b) Since high titers of anti-GM1, GM2, and GD1b antibodies in humans appear to selectively destroy motor neuron-muscle synaptic contacts and cause motor neuron disease, we will study the role of gangliosides in regulating Ca2+, second messengers and synaptogenesis. c) We will determine the point mutations in the beta-Hex gene in patients with partial deficiency of the GM2-ganglioside degrading enzyme N-acetyl-beta-D-glucosaminidase (beta-Hex) in order to understand more about beta-Hex, how enzymes degrade GSL, and how better remedial therapy might be designed.
| Qin, Jingdong; Kilkus, John P; Dawson, Glyn (2018) The cross roles of sphingosine kinase 1/2 and ceramide glucosyltransferase in cell growth and death. Biochem Biophys Res Commun 500:597-602 |
| Getz, Ted; Qin, Jingdong; Medintz, Igor L et al. (2016) Quantum dot-mediated delivery of siRNA to inhibit sphingomyelinase activities in brain-derived cells. J Neurochem 139:872-885 |
| Qin, Jingdong; Kilkus, John; Dawson, Glyn (2016) The hyaluronic acid inhibitor 4-methylumbelliferone is an NSMase2 activator-role of Ceramide in MU anti-tumor activity. Biochim Biophys Acta 1861:78-90 |
| Dawson, Glyn (2016) Quantum dots and potential therapy for Krabbe's disease. J Neurosci Res 94:1293-303 |
| Walters, Ryan; Medintz, Igor L; Delehanty, James B et al. (2015) The Role of Negative Charge in the Delivery of Quantum Dots to Neurons. ASN Neuro 7: |
| Agarwal, Rishabh; Domowicz, Miriam S; Schwartz, Nancy B et al. (2015) Delivery and tracking of quantum dot peptide bioconjugates in an intact developing avian brain. ACS Chem Neurosci 6:494-504 |
| Dawson, Glyn (2015) Measuring brain lipids. Biochim Biophys Acta 1851:1026-39 |
| Testai, Fernando D; Xu, Hao-Liang; Kilkus, John et al. (2015) Changes in the metabolism of sphingolipids after subarachnoid hemorrhage. J Neurosci Res 93:796-805 |
| Dawson, Glyn (2014) Glycosignaling: a general review. Adv Neurobiol 9:293-306 |
| Testai, Fernando D; Kilkus, John P; Berdyshev, Evgeny et al. (2014) Multiple sphingolipid abnormalities following cerebral microendothelial hypoxia. J Neurochem 131:530-40 |
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