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Meghan Ferrall-Fairbanks
PhD Defense Presentation
Date: Thursday, July 27th, 2017
Time: 3pm EST
Location: Engineered Biosystems Building (EBB), CHOA Seminar Room
Committee Members:
Manu O. Platt, PhD (BME, Georgia Institute of Technology) (Advisor)
Rashid Bashir, PhD (Bioengineering, University of Illinois Urbana-Champaign)
Melissa L. Kemp, PhD (BME, Georgia Institute of Technology)
Ellen Moomaw, PhD (Chemistry & Biochemistry, Kennesaw State University)
Eberhard O. Voit, PhD (BME, Georgia Institute of Technology)
Title:
Effects of Cathepsin Proteolytic Network Dynamics on Extracellular Matrix Degradation in Biological Machines and Invasive Disease
Abstract:
Proteases are enzymes that degrade proteins and play a major role in cellular homeostasis. When proteins are aged, defective, or just extracellular proteins taken up by the cell, the majority of these proteins are degraded by enzymes in the lysosomes, such as cysteine cathepsins. In addition to their proteolytic activity inside lysosomes, cathepsins can be secreted from cells and degrade extracellular matrix (ECM) with differing affinities in a variety of tissue destructive diseases such as cancer, atherosclerosis, and osteoporosis. These potent enzymes are known to be upregulated in tissue destructive diseases, but researchers have been limited in their ability to successfully target cathepsin dysfunction in these diseases. It is important that we not only understand how these enzymes remodel the extracellular matrix, but also how these proteases interact with each other, to effectively dose pharmaceutical inhibitors to regulate cathepsin dysfunction therapeutically. The objective of this research was to develop a mechanistic understanding of how cathepsins interact with ECM and each other for tissue remodeling as produced and regulated by living cells, as a means to target these cathepsin mechanisms in the treatment of tissue destructive diseases and remodeling of synthetic environments. The central hypothesis of this research was that when cells secrete multiple species of cathepsins, these cathepsins exhibit complex cathepsin-cathepsin interactions between potent cathepsins K, L, S, and V, which reduces expected ECM protein degradation and thus concentrations of cathepsins. This work developed a mechanistic model to quantify the interactions between cathepsins and extracellular matrix substrates collagen and elastin, designed mutations to interrupt cathepsin-cathepsin interactions, and explored the role of proteolysis in destabilizing the fibrin-based matrix of locomoting biological machines.
