O-glycosylation of serine and threonine of nuclear and cytoplasmic proteins by a single beta-N- acetyl-D-glucosamine moiety (O-GlcNAc) is a ubiquitous post-translational modification that is highly dynamic and fluctuates in response to cellular stimuli. O-GlcNAc often competes with protein phosphorylation, and these two modifications have extensive crosstalk in the regulation of signaling, transcription, and the functions of oncogenes and tumor suppressors. Diabetes, the biological driver for this application, is a prime example of a disease where increased levels of insulin resistance, inhibition of the anti-apoptotic action of insulin, alteration of circulating O-GlcNAc is known to disrupt normal signaling, and has been associated with the induction of adipocytokine levels, deregulation of gluconeogenesis, and modulation of insulin gene transcription. We will utilize a new immunogen strategy to develop site-specific O-GlcNac antibodies to four sites of O-GlcNAc modification on three proteins that play a role in signaling suppression in diabetes. Consequently, if we are successful, the mAbs generated in this initial study will have an immediate impact on diabetes research in addition to providing a test system for this strategy. We predict that at the end of phase 1, we will have demonstrated a strategy that will allow GlycoScientific to produce a wide range of O-GlcNAc site-specific MAbs, at a known and contained cost. We feel that these will have far reaching implications in disease research.

Public Health Relevance

O-glycosylation of serine and threonine of nuclear and cytoplasmic proteins by a single beta-N- acetyl-D-glucosamine moiety (O-GlcNAc) is a ubiquitous post-translational modification that is highly dynamic and fluctuates in response to cellular stimuli. O-GlcNAc often competes with protein phosphorylation, and these two modifications have extensive crosstalk in the regulation of signaling, transcription, and the functions of oncogenes and tumor suppressors. Diabetes, the biological driver for this application, is a prime example of a disease where increased levels of insulin resistance, inhibition of the anti-apoptotic action of insulin, alteration of circulating O-GlcNAc is known to disrupt normal signaling, and has been associated with the induction of adipocytokine levels, deregulation of gluconeogenesis, and modulation of insulin gene transcription. We will utilize a new immunogen strategy to develop site-specific O-GlcNac antibodies to four sites of O-GlcNAc modification on three proteins that play a role in signaling suppression in diabetes. Consequently, if we are successful, the mAbs generated in this initial study will have an immediate impact on diabetes research in addition to providing a test system for this strategy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
Project #
5R41GM104631-02
Application #
8546432
Study Section
Special Emphasis Panel (ZRG1-IMST-G (10))
Program Officer
Sheeley, Douglas
Project Start
2012-09-17
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$301,575
Indirect Cost
Name
Glycoscientific, LLC
Department
Type
DUNS #
829734347
City
Athens
State
GA
Country
United States
Zip Code
30602