Effects of cathepsin proteolytic network dynamics on extracellular matrix degradation in biological machines and invasive disease

Cathepsin;Extracellular matrix;Proteolytic network;Biological machines;Computational modeling;Tissue remodeling

Ferrall-Fairbanks, Meghan C. ; Platt, Manu O. Biomedical Engineering (Joint GT/Emory Department) Bashir, Rashid Kemp, Melissa L. Moomaw, Ellen Voit, Eberhard O. ; Platt, Manu O.

University:Georgia Institute of Technology

Department:Biomedical Engineering (Joint GT/Emory Department)

关键词: Cathepsin;    Extracellular matrix;    Proteolytic network;    Biological machines;    Computational modeling;    Tissue remodeling;   

Others  :  https://smartech.gatech.edu/bitstream/1853/60657/1/FERRALL-FAIRBANKS-DISSERTATION-2017.pdf

美国|英语

来源: SMARTech Repository

【 摘 要 】

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, these proteins are degraded by enzymes in the lysosomes, such as cysteine cathepsins. In addition to their proteolytic activity inside lysosomes, cathepsins secreted from cells degrade extracellular matrix (ECM) with differing affinities in tissue destructive diseases. 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 to not only understand how these enzymes remodel the ECM, but also how these proteases interact with each other, to effectively dose 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. With the hypothesis that cells secrete multiple species of cathepsins, which exhibit complex cathepsin-cathepsin interactions between potent cathepsins K, L, S, and V, which reduces the concentrations of cathepsins and thus expected protein degradation. This work developed a mechanistic model to quantify the interactions between cathepsins and ECM substrates, designed mutations to interrupt cathepsin-cathepsin interactions, and explored the role of proteolysis in destabilizing the fibrin-based matrix of biological machines.