In the presence of unusually high levels of these enzymes, some proteins tend to form denser clusters than normal in vivo. If the aggregates grow in size, it can lead to a build-up of insoluble plaques that can block neurovascular transport and cause neural cell death.
"If higher TGase concentrations in cerebrospinal fluid and in the brain lead to protein agglomeration, then their inhibition could reduce symptoms, delay the onset of agglomeration, and maintain viable neural cell health extending the quality of life for those afflicted," hypothesizes Brian Love, a professor of materials science and engineering (MSE) at Virginia Tech.
Love, who focuses his research on tissue and cell engineering, and Elena Fernandez Burguera, a post-doctoral research associate, are evaluating specific therapies to fight the abnormally high TGase binding. Based upon the prior work of several others who are conducting clinical trials, Love and Burguera are developing an in vitro model to evaluate the ability of several inhibitors to block protein aggregation by TGases.
Again, based on the work of other scientists, "several compounds show some positive effects," Love says. These include creatine, cystamine hydrochloride, and a few others. "The development of an inhibition protocol may help test the efficacy of other inhibitors as well," the engineer adds.
The Virginia Tech researchers are looking at the enzymatic binding of protein-bound polystyrene particles as models. Groups of particles are dispersed in calcium-rich aqueous solutions containing TGases. Once mixed, the particle binding begins. The bigger agglomerates attempt to settle out of the solution, and Love and Burguera track particle sedimentation.
The tracking method, called Z-axis Translating Laser Light Scattering (ZATLLS), is unique to Virginia Tech and based on key concepts in transport phenomena. It has been used to gauge how other complex fluids, such as paints and sealants, are dispersed. Now Love and Burguera are resolving when protein coated particles are effectively dispersed in vitro and under what conditions they are unstable enough to agglomerate.
They track in situ sedimentation of protein-coated particles exposed to transglutaminase, both in the presence of and without transglutaminase inhibitors. "We can use ZATLLS to resolve whether inhibitors prevent agglomeration of protein coated particles by TGase if the inhibitors lower the particle sedimentation velocity," Love says. "Our goal is to find the safest and most effective inhibitors that prevent the agglomeration-based crosslinking found throughout these neurological disorders."
This work is funded by the Commonwealth Health Research Board.
Love is a participating member in the School of Biomedical Engineering and Science (SBES), a joint venture between Virginia Tech's College of Engineering and the Wake Forest University School of Medicine. SBES is the partnership of the two eminent educational institutions. Virginia Tech's highly acclaimed engineering college has long been the university's educational centerpiece. Since 1987, when U.S. News & World Report starting ranking the top undergraduate engineering program, and later, the graduate schools, Virginia Tech's College of Engineering has consistently appeared in the magazine's listings. And, today, the National Science Foundation lists the College among the top 15 for research expenditures. Wake Forest University Baptist Medical Center gained nearly $10 million in funding from the National Institutes of Health (NIH) for the fiscal year that ended on Sept. 30, 2004, reaching $114,768,124 and ranking 36th overall among 125 American medical schools.
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