“What’s Eating You?” Quantifying Proteolytic Activity in Health and Disease with Novel Assays and Computational Models

Mathematical Biology and Ecology Seminar
Wednesday, October 19, 2011 - 11:00
1 hour (actually 50 minutes)
Skiles 006
Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University
Cathepsins are enzymes that can cleave collagen and elastin, major structural proteins of tissue and organs, and participate in tissue-destructive disease progression seen in osteoporosis, arthritis, atherosclerosis, and cancer metastasis.  Detection of mature cathepsins and quantification of specific activity have proven difficult due to instability of the mature, active enzyme extracellularly, which has led to them being overlooked in a number of diseases.  During this seminar, Dr. Platt will discuss the important development of a reliable, sensitive method to detect the activity of mature cathepsins K, L, S, and V.  Then he will focus on their progress towards developing a comprehensive computational model of cathepsin-mediated degradation of extracellular matrix, based on systems of ordinary differential equations.  From the computational model and experimental results, a general assumption of inertness between familial enzymes was shown to be invalid as it failed to account for the interaction of these proteases among themselves and within their microenvironment.  A consequence of this was significant overestimation of total degradative potential in multiple cathepsin reaction systems. After refining the system to capture the cathepsin interactive dynamics and match the experimental degradation results, novel mechanisms of cathepsin degradation and inactivation were revealed and suggest new ways to inhibit their activity for therapeutic benefit.