Functions of O-glycans: In collaboration with Stasia Anderson, Daryl Despres and M Starost (NIH), we have continued studies, in collaboration with the Ten Hagen lab (NIH), on the cardiac phenotypes resulting from the deletion of GalNAcT-1. We have found that the heart valves are markedly enlarged in the affected hearts. We are analyzing the underlying molecular cause(s) for this phenotype. Tom Beres in collaboration with the Angerer lab (NIH), is examining the roles of GalNAc-Ts and mucin-type O-glycosylation during embryonic development of the sea urchin, S. purpuratus. Two phenotypes are being characterized in morphants in which GalNAcT-7 expression is ablated. One phenotype involves the loss of muscle, and the other, embryos lack both the ciliated band (cells with cilia that sweep food into the mouth) and the network of nerves normally present in this region. Tom, together with Divya Patel, is looking at the effects of T7 morpholinos on several signal transduction pathways potentially involved in muscle development, including WNT, Notch, and TGF-beta. Tom has also been characterizing O-glycans present during sea urchin development using lectin staining of whole embryos, as well as lectin blotting using embryonic extracts. Raul Rojas, using conventional confocal microscopy, in combination with a novel fast and automated post-imaging protocol (developed in collaboration with Dr. George Pattersons lab, NIBIB) is locating the GalNAcT-s within the different regions of the Golgi. Raul has also set up the use of FRET microscopy to detect interaction of proteins within organelles of the biosynthetic pathway. 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 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.
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