“What’s Eating You?” Quantifying Proteolytic Activity in Health and Disease with Novel Assays and Computational Models
Abstract
Cathepsins are enzymes with the most powerful human collagenase and elastase activity that are upregulated
at sites of normal tissue remodeling and during tissue-destructive disease progression. We study them in the
context of tissue remodeling in cancer progression and cardiovascular diseases such as sickle cell disease and
atherosclerosis. They are synthesized as stable inactive precursors requiring activation by propeptide
cleavage, and detection of mature cathepsins and quantification of specific activity have proven difficult due
to instability of the mature, active enzyme extracellularly, diminishing appreciation for their involvement in a
large number of diseases. During this seminar, we will discuss our studies of this family of powerful proteases
in diseases with particular attention to cancer and sickle cell disease. First, we will discuss the important
development of a reliable, sensitive method of zymography to detect the activity of mature cathepsins K, L, S,
and V and integrating that assay with the development of a computational kinetic model to predict cathepsin-mediated
tissue remodeling by cells during advancing disease. Secondly, we will discuss our applications of
these technologies and potential use as both diagnostic and prognostic indicators of human breast, lung, and
cervical cancer as well as newly identified mechanisms of cathepsin activity in complications of stroke in
children with sickle cell disease.