Functions of O-glycans: In collaboration with Stasia Anderson, Daryl Despres and M Starost from NIH, Yu Guan has studied the cardiac phenotypes resulting from the deletion of GalNAcT-1. She found that the heart/body weight ratio was increased in 4-month-old KO animals compared to heterozygotes and wild-type littermate controls. Histological analysis revealed right or left ventricle hypertrophy, enlarged cardiomyocytes, increased interstitial fibrosis, and mitochondria swelling and dissolution in knockout animals. Further analysis revealed that the heart valves are markedly enlarged in the affected hearts. Yu is analyzing the underlying molecular cause(s) for this phenotype. We continue to collaborate with Suzanne Walker (Harvard) to identify small molecule inhibitors of GalNAcTs. We are performing biological assays on cell lines with candidate inhibitors. We have a series of collaborations with investigators around the world to assess/phenotype various mouse models in which the expression of specific GalNAcTs have been ablated. This includes work with Jesse Mager to evaluate role of GalNAcT-3 in sperm development and maturation, studies with A.G. Holleboom and J.A. Kuivenhoven on the role of GalNAcT-2 on the control of lipids, and with Q. Zheng on the function of GalNAcT-2 on otitis media. Mechanisms of GalNAcT function: We are collaborating with L. Masgrau to use the hybrid QM/MM (quantum mechanics/molecular mechanics) approach to study the retaining mechanism used by GalNAcTs in forming O-glycans.

Project Start
Project End
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Budget End
Support Year
1
Fiscal Year
2012
Total Cost
$911,983
Indirect Cost
Name
National Institute of Dental & Craniofacial Research
Department
Type
DUNS #
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