Meghan Ferrall

PhD Proposal Presentation

Day: Wednesday, June 3, 2015

Time: 10:00am

Location: Molecular Science & Engineering (MSE) 1222

Thesis 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. Cathepsins are a family of understudied proteases that have the human body’s most potent collagenase and elastase. Previous work shows cathepsin S preferentially degrades cathepsin K, reducing the degradation of collagen. This process is termed cathepsin cannibalism. Moreover, once these proteins are secreted by cells, they are subject to reaction diffusion kinetics, cell surface kinetics, and some other unidentified interactions, that all must be considered beyond traditional extracellular matrix degradation kinetics. Cathepsins are also secreted with a propeptide covering the enzyme’s active site, which is cleaved to activate the enzyme. Cells produce cystatins, endogenous cathepsin inhibitors, to control proteolytic activity by these enzymes.

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, in order to effectively dose pharmaceutical inhibitors to regulate cathepsin dysfunction therapeutically.  The objective of this proposalis 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. Therefore, the central hypothesis of this proposal is 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. The research proposal is innovative because it analyzes cathepsin activity through molecular and computational approaches to develop mechanistic models to drive effective targeting strategies for cathepsin-mediated diseases and sustainable fabrication of biological machines.