Several neurologically based afflictions, such as Huntington’s,Parkinson’s, and Alzheimer diseases, have been correlated to a higherthan normal presence of a specific type of enzymes, calledtransglutaminases (TGase) in the human body. TGases, whose function isto catalyze covalent bonds among proteins, are commonly found inseveral different human tissues.
In the presence of unusually high levels of these enzymes, someproteins tend to form denser clusters than normal in vivo. If theaggregates grow in size, it can lead to a build-up of insoluble plaquesthat can block neurovascular transport and cause neural cell death.
"If higher TGase concentrations in cerebrospinal fluid and in thebrain lead to protein agglomeration, then their inhibition could reducesymptoms, delay the onset of agglomeration, and maintain viable neuralcell health extending the quality of life for those afflicted,"hypothesizes Brian Love, a professor of materials science andengineering (MSE) at Virginia Tech.
Love, who focuses his research on tissue and cell engineering, andElena Fernandez Burguera, a post-doctoral research associate, areevaluating specific therapies to fight the abnormally high TGasebinding. Based upon the prior work of several others who are conductingclinical trials, Love and Burguera are developing an in vitro model toevaluate the ability of several inhibitors to block protein aggregationby TGases.
Again, based on the work of other scientists, "several compoundsshow some positive effects," Love says. These include creatine,cystamine hydrochloride, and a few others. "The development of aninhibition protocol may help test the efficacy of other inhibitors aswell," the engineer adds.
The Virginia Tech researchers are looking at the enzymatic bindingof protein-bound polystyrene particles as models. Groups of particlesare dispersed in calcium-rich aqueous solutions containing TGases. Oncemixed, the particle binding begins. The bigger agglomerates attempt tosettle out of the solution, and Love and Burguera track particlesedimentation.
The tracking method, called Z-axis Translating Laser LightScattering (ZATLLS), is unique to Virginia Tech and based on keyconcepts in transport phenomena. It has been used to gauge how othercomplex fluids, such as paints and sealants, are dispersed. Now Loveand Burguera are resolving when protein coated particles areeffectively dispersed in vitro and under what conditions they areunstable enough to agglomerate.
They track in situ sedimentation of protein-coated particles exposedto transglutaminase, both in the presence of and withouttransglutaminase inhibitors. "We can use ZATLLS to resolve whetherinhibitors prevent agglomeration of protein coated particles by TGaseif the inhibitors lower the particle sedimentation velocity," Lovesays. "Our goal is to find the safest and most effective inhibitorsthat prevent the agglomeration-based crosslinking found throughoutthese neurological disorders."
This work is funded by the Commonwealth Health Research Board.
Love is a participating member in the School of BiomedicalEngineering and Science (SBES), a joint venture between Virginia Tech’sCollege of Engineering and the Wake Forest University School ofMedicine. SBES is the partnership of the two eminent educationalinstitutions. Virginia Tech’s highly acclaimed engineering college haslong been the university’s educational centerpiece. Since 1987, whenU.S. News & World Report starting ranking the top undergraduateengineering program, and later, the graduate schools, Virginia Tech’sCollege of Engineering has consistently appeared in the magazine’slistings. And, today, the National Science Foundation lists the Collegeamong the top 15 for research expenditures. Wake Forest UniversityBaptist Medical Center gained nearly $10 million in funding from theNational Institutes of Health (NIH) for the fiscal year that ended onSept. 30, 2004, reaching $114,768,124 and ranking 36th overall among125 American medical schools.
The above post is reprinted from materials provided by Virginia Tech. Note: Materials may be edited for content and length.
Cite This Page: