Abstract

We are studying the events that occur due to the inability to degrade lipid substrated in the sphingolipidoses. We are using both mouse and human model systems. In the mouse system, we are using cultured neurons from a model model of Sandhoff disease and analyzing the changes in gene expression by RNA-seq. Functional assessment of the genes that are altered in the disease neurons will be accomplished by an in vivo pooled genetic screening approach. In the human system, iPS cells from a Sandhoff disease patient were edited with CRISPR/CAS9 to enable the correction of the HEXB gene. Using the Sandhoff disease and corrected iPS cells, cerebral organoids were produced. The organoids are being studied to identify changes caused by the genetic defect in Sandhoff disease that may lead to alterations in brain development.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIADK056016-12
Application #
9775041
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
U.S. National Inst Diabetes/Digst/Kidney
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Allende, Maria L; Cook, Emily K; Larman, Bridget C et al. (2018) Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation. J Lipid Res 59:550-563
Spiegel, Sarah; Proia, Richard L (2016) In Memoriam: Roscoe Owen Brady (1923-2016). J Lipid Res :
Weth-Malsch, Daniela; Langeslag, Michiel; Beroukas, Dimitra et al. (2016) Ablation of Sphingosine 1-Phosphate Receptor Subtype 3 Impairs Hippocampal Neuron Excitability In vitro and Spatial Working Memory In vivo. Front Cell Neurosci 10:258
Regier, Debra S; Proia, Richard L; D'Azzo, Alessandra et al. (2016) The GM1 and GM2 Gangliosidoses: Natural History and Progress toward Therapy. Pediatr Endocrinol Rev 13 Suppl 1:663-73
Proia, Richard L; Hla, Timothy (2015) Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. J Clin Invest 125:1379-87
Gupta, Sita D; Gable, Kenneth; Alexaki, Aikaterini et al. (2015) Expression of the ORMDLS, modulators of serine palmitoyltransferase, is regulated by sphingolipids in mammalian cells. J Biol Chem 290:90-8
Blaho, Victoria A; Galvani, Sylvain; Engelbrecht, Eric et al. (2015) HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation. Nature 523:342-6
Weth, Daniela; Benetti, Camilla; Rauch, Caroline et al. (2015) Activated platelets release sphingosine 1-phosphate and induce hypersensitivity to noxious heat stimuli in vivo. Front Neurosci 9:140
Allende, Maria Laura; Proia, Richard L (2014) Simplifying complexity: genetically resculpting glycosphingolipid synthesis pathways in mice to reveal function. Glycoconj J 31:613-22
Novgorodov, Sergei A; Riley, Christopher L; Yu, Jin et al. (2014) Essential roles of neutral ceramidase and sphingosine in mitochondrial dysfunction due to traumatic brain injury. J Biol Chem 289:13142-54

Showing the most recent 10 out of 16 publications