GLYN DAWSON Biographical Sketch

Glyn Dawson, PhD.          Professor

University of Bristol, England    B.Sci.     07/1964       Biological Chemistry

University of Bristol, England     Ph.D.     01/1968      Biochemistry

A.  Personal statement

I have been training researchers in the sphingolipid, lysosomal hydrolase and membrane signaling fields for 40 years and believe I have made significant impact.

*I pioneered the use of Mass-Spectrometry for sphingolipid analysis in the late 60s, worked on its development in the 1970s and have recently come back to using it to identify bioactive sphingolipid components of cells and lipid rafts and how they impact their targets.

*We have demonstrated the importance of sphingolipids in mental retardation and the recent development of Spingosine-1-phosphate analog drugs such FTY720 (which inhibits sphingomyelinase) and glucosyltransferase inhibitors (eg: Epiglustat) has shown that we can use sphingolipid-modifying drugs to treat human disease such as Multiple sclerosis and cancer.

*We have found that CNS brain cells actively recycle sphingosines rather than degrading them by the lyase pathway and this is an important new concept which can explain why some gene mutations present as peripheral nerve rather than central nerve (CNS) problems.  

*We use the Lipid Microdomain concept (Rafts) to understand how signaling molecules enhance cell death programs and how CNS-active drugs can regulate this.

*By making mice with conditional knockouts of glycosyltransferases, by using PCR gene screening of brain tumors to identify sphingolipid targets and by studying sphingolipids in brains and isolated brain cell cultures we have impacted the way we view these molecules.  The discovery of an animal model for neutral sphingomyelinase deficiency-.which resembles osteogenesis imperfecta-has also changed the way we think about membranes and the extracellular matrix.

*Although gene therapy, stem cell therapy and enzyme replacement therapy have all been tried, there has been no success in reversing or even stabilizing the neurodegeneration in CNS storage diseases, so our approach has been to attach specific peptides and proteins to nanoparticles (Quantum dots) and use chemistry to both direct and follow them to their target cells and subcellular locations. The barrier to progress here is that enzyme or sphingolipid-modifying drugs do not cross the human blood-brain barrier or spread much beyond the initial injection site.  However, when we attach a novel class of drugs (with the unique property of being able to escape the endosomal uptake system) to the Quantum dots we can deliver sphingolipid-modifying (and other) cargo specifically to neurons.  

* Our approach to treating mental retardation is to combine cell biochemistry and genetics with peptide chemistry and nanotechnology and we expect this combination to have a significant impact in the treatment of human disease.

*The Lab provides an excellent training environment for undergraduate, graduate and postgraduate students interested in applying basic lipid biochemical tools to translational research.

B.Positions and Honors

Professional Experience:

l967-69  Postdoctoral Fellow, Grad. School of Public Health, Univ. of Pittsburgh, PA.

l969-74   Assistant Professor of Pediatrics and Biochemistry, University  of Chicago.

l975-        Associate Professor of Pediatrics and Biochemistry, University of Chicago

l985-        Professor, Departments of Pediatrics, Biochemistry and Molecular Biology, University of Chicago.

Awards and Advisory Committees:

l96l-64        U.K. State Scholarship; University of Bristol

l97l              Member, National Tay-Sachs Association Advisory Board

l975-79        USPHS DRG Neurology A Study Section

l975-80        USPHS Research Career Development Award, (NS 00029)

l979-80         John Simon Guggenheim Foundation Fellowship Award

l984-88         Neurological Science Study Section (NLS-1)

1987-            Neuronalceroidlipofuscinosis (Batten) Advisory Board

1986, 1992    Burroughs-Wellcome Fellow

1988-93         J. Biol. Chem. Editorial Board

1990-97          Neuro C Study Section (initially ad-hoc)

1997-01           Molecular, Developmental, Cellular Neurosciences ..                      Study Section (MDCN-2).

2006-08           CNBT Study Section

2010-               Member CMBG Study section

C. 15 Selected Recent Peer-Reviewed Publications relevant to this proposal

Kilkus, J, Goswami, R, Testai FD, Dawson, G. (2003) Ceramide in rafts (detergent-insoluble fraction) mediates cell death in neurotumor cell lines. J Neurosci. Res., 72(1) 62-75. http://www.ncbi.nlm.nih.gov/pubmed/12645080

Testai, F.D., Landek, M.A. and Dawson, G. (2004). Regulation of sphingomyelinases in cells of the oligodendrocyte lineage. J. Neurosci. Res. 75: 66-74. http://www.ncbi.nlm.nih.gov/pubmed/14689449

Testai, F.D., Landek, M.A, Goswami, R., Ahmed, M., and Dawson, G. (2004).  Acid sphingomyelinase and inhibition by phosphate ion: role of PtdIns(3,4,5)P3 in oligodendrocyte signaling. J. Neurochem. 89: 636-644

Goswami, R., Singh, D., Phillips, G., Kilkus, J., and Dawson, G (2005). Ceramide regulation of the tumor supressor phosphatase PTEN in Rafts isolated from neurotumor cell lines. J. Neurosci. Res. 81: 541-550.

Qin,,J.,  Goswami,R, Balabanov, R, and  Dawson, G., (2007). Oxidized phosphatidylcholine (OxPC) is a marker for neurodegeneration multiple sclerosis brain .J. Neurosci Res. 85: 977-984.

Qin J, Goswami R, Dawson S, Dawson G. (2008) Expression of the receptor for advanced glycation end products in oligodendrocytes in response to oxidative stress. J Neurosci Res. 86: 2414-2422. PMCID: PMC2671024

Qin J, Testai FD, Dawson S, Kilkus J, Dawson G. (2009) Oxidized phosphatidylcholine formation and action in oligodendrocytes. J Neurochem.;110(5):1388-99. PMID: 20215115

Saadat L, Dupree JL, Kilkus J, Han X, Traka M, Proia RL, Dawson G, Popko B. (2009) Absence of oligodendroglial glucosylceramide synthesis does not result in CNS myelin abnormalities or alter the dysmyelinating phenotype of CGT-deficient mice. Glia. 58: 391-298. PMCID: PMC2807477

Qin, J., Berdyshev, E, Goya, J, Natarajan, V and Dawson G (2010) Neurons and oligodendrocytes recycle sphingosine-1-phosphate to ceramide; significance for apoptosis and multiple sclerosis. J. Biol. Chem. 285: 14134-14143. PMID: 20215115

Delehanty, J.B. , C.E. Bradburne, K. Boeneman, K. Susumu, D. Farrell, B.C. Mei, J.B. Blanco-Canosa, G. Dawson, P.E. Dawson, H. Mattoussi, I.L. Medintz, (2010)  Delivering quantum dot-peptide bioconjugates to the cellular cytosol: escaping from the endolysosomal system, Integr. Biol. (Camb) 2: 265-277.

Dawson, G., Schroeder, C., and Dawson, P.E (2010) Palmitoyl:protein thioesterase (PPT1) inhibitors can act as pharmalogical chaperones in infantile Batten disease. Biochem. Biophys. Res. Commun. 395: 66-69.

Dawson, G. and Qin, J (2011) Gilenya (FTY720) inhibits acid sphingomyelinase by a mechanism similar to    tricyclic antidepressants. Biochem. Biophys. Res. Commun. 404: 321-323.

Qin J, Berdyshev E, Poirer C, Schwartz NB, Dawson G.  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. 2012 Apr 20;287(17):13620-32. doi: 10.1074/jbc.M111.304857. Epub 2012 Mar 1.

Dawson G, Fuller M, Helmsley KM, Hopwood JJ. (2012)Abnormal gangliosides are localized in lipid rafts in Sanfilippo (MPS3a) mouse brain.Neurochem Res;37(6):1372-80.

Walters R, Kraig RP, Medintz I, Delehanty JB, Stewart MH, Susumu K, Huston AL, Dawson PE, Dawson G. (2012) Nanoparticle Targeting to Neurons in a Rat Hippocampal Slice Culture Model. ASN Neuro.

Qin J, Dawson G. (2012) Evidence for coordination of lysosomal (ASMase) and plasma membrane (NSMase2) forms of sphingomyelinase from mutant mice.FEBS Lett.;586(22):4002-9. PMID:23046545

D.  Research Support:

Ongoing Research Support:

R01 NS036866 (Dawson)                                               05/1/11-04/30/16

NIH/NINDS

Glycosphingolipids and Mental Retardation

The broad, long-term objectives are to understand the role of glycolipids (glycosphingolipids (GSL) and inositolphosphoglycerides) in normal nervous function and the pathogenic processes involving them which lead to mental retardation. To achieve this goal we 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.

Role:  Principal Investigator

P30 HD054275 (Schwartz)                09/15/06–08/31/11                               

NIH/NICHD

J.P. Kennedy Mental Retardation and Developmental Disabilities Center

The overall objective of the Mental Retardation and Developmental Disabilities Center is to provide a structure and Core facilities that support and foster interdisciplinary programs in biomedical and biobehavioral research relevant to MRDD.

Role:  Director Subcore D1

P01 HD009402 (Schwartz)                                        04/01/11 thru 3/31/16.

NIH/NICHD

Biological Basis of Mental Retardation

Project 3 is aimed at understanding the biochemical pathology of Infantile Batten disease (a devastating mental retardation syndrome), using chemical chaperones to treat lymphoblastoid cell lines and fibroblast cultures from patients and neural tissue culture systems similar to those used in NS036866.

Role: Principal Investigator on Project 3: Pathogenesis of Batten Disease

Recent Completed Research Support:

R01 NS027336 (Popko)                        12/15/04-11/30/08           

NIH/NINDS

Genetic Analysis of Glycan Function in Myelinating Cells

These studies are designed to use a genetic approach to explore the function of glycosylated lipids and proteins in PNS and CNS myelinating cell development, the myelination process, and in the stability of the myelin sheath.

Role:  Co-Investigator

K12 HD043387 (Goldstein)                                    04/11/03–11/30/08

NIH/NICHD

Research Career Training in Pediatrics

The overall goal of the program is to train pediatricians for careers in research in the areas of human genetics, growth and development, and the cellular and molecular mechanisms of disease.

Role: Co-Program DirectorGLYN DAWSON