“Very little is known about the intracellular dynamics between genes, proteins and the metabolic pathways that guide either normal processes or give rise to abnormalities,” said Grande-Allen. “Accumulative efforts in our lab involve investigations into valve cell morphology and disease from a more mechanical perspective. Specifically, we look for cues as to how alterations to cells and cellular environments are driven by mechanical stress of the pumping heart over many years.”
In a unique twist of fate, Grande-Allen, graduate student Dena Wiltz, and undergraduate student Aditya Kumar found that Gentamicin, an aminoglycosidic antibiotic used to treat many types of bacterial infections, significantly reduced the number and size of calcific nodules formed by valvular interstitial cells.
The research, which was detailed in the journal Cardiovascular Engineering and Technology, was initially spurred by the lab’s examination of various antibiotics for the occasional prevention of bacterial infections in cell cultures.
“Contamination of cell cultures is a consistent issue for researchers. Impurities not only adversely affect results, but vast amounts of time and money can be spent managing bacterial contaminates,” said Wiltz, a sixth-year graduate student in the Grande-Allen lab at Rice’s BioScience Research Collaborative whose research in valve disease is supported by a grant from Baylor College of Medicine. “Gentamicin is widely used for the in vitro prevention of cell and tissue culture contamination, but it has been reported to affect calcium levels in various cell types. So we decided to add it to our cultures – not to prevent contamination so much as to see if it regulated calcium mineralization by valve cells.”
Their investigations paid off. “Not only did we find that dose-dependent increases of Gentamicin caused alterations to cellular mineralization, but the findings, along with a literary investigation, spurred insight into the roles cellular components, such as lipids and mitochondria, might play in the development of pathological calcification,” added Kumar, who is a Rice senior and co-author on the research paper. He has been a member of the Grande-Allen group since the summer of his freshman year.
Aortic valve tissue is made up of trilayered connective tissues, and Grande-Allen and her students apply engineering analysis to decode how individual parts of this complex cooperate, respond to cellular signals, and are influenced by overall valvular function, growth and the evolution of abnormalities.
“Through a bottom up approach, we are looking at how valvular interstitial cells – the primary cells within these tissue layers – interact both biologically and mechanically with their surrounding environments,” explained Grande-Allen. “Although Gentamicin has limited clinical use due to its toxic side effects, our results might prove to be useful in connecting these processes, and ultimately in the development of promising pharmaceuticals that curb the progression of heart-valve disease.”
The research was also supported by an NIH grant from the National Heart, Lung, and Blood Institute (NHLBI).