Azouz Research Lab
The Azouz Lab investigates the function and regulation of proteases in host defense and in the onset and propagation of inflammatory and allergic diseases. The function of proteases is irreversible and therefore highly regulated, particularly by protease inhibitors coupling to the proteases. Protease–protease inhibitor coupling limits the proteolytic activity and initiation of signaling pathways by the protease. Proteases and protease inhibitors are well known for their important regulatory roles in the coagulation system, fibrinolysis and complement system.
The Azouz Lab focuses on deciphering the role of proteases and their inhibitors in the epithelium as part of homeostatic and surveillance mechanisms. As loss of protease inhibitors and alterations of proteolytic activity lead to tissue damage and may exert a paramount signal in the development of inflammatory diseases, the Azouz Lab also focuses on deciphering the molecular mechanisms that disrupt the balance between proteases and protease inhibitors and developing strategies for controlling proteolytic activity as an approach to treat immune diseases.
Why do we investigate the epithelial barrier?
A breakdown of immunologic tolerance appears to be a key feature in allergic diseases. The mechanisms underlying the break of tolerance are not well understood and involve a combination of environmental and genetic factors. The epithelium is the first line of defense against potential insults, providing a physical barrier between the host and the external environment. The importance of epithelial integrity in the development of allergic disease is supported by clinical observations of atopic or allergic march, which is the natural history or typical progression of allergic diseases that often begin early in life. These include atopic dermatitis (eczema), food allergy, allergic rhinitis (hay fever) and asthma. At a barrier breach, harmless antigens may encounter immune cells, potentially leading to production of a danger signal and priming a break in immune tolerance and an allergic response. The Azouz Lab investigates the mechanisms by which protease–protease inhibitor imbalance promotes barrier breaches and loss of immunologic tolerance in the development of allergic diseases.
Esophageal Allergy as Protease-mediated Disease
An imbalance of specific proteins, proteases and protease inhibitors, in cells lining the esophagus may cause inflammation and tissue damage in people with eosinophilic esophagitis (EoE). In people with active EoE, biopsies of esophageal tissues show a near-complete lack of the protease inhibitor SPINK7, which normally damps down inflammation and helps preserve tissue structure. In this study, researchers of the Azouz Lab and Rothenberg CURED Lab found a missing link that further explains how the process works. SPINK7 normally binds with the protease KLK5, keeping it in check. Without enough SPINK7, KLK5 is free to degrade tissues and start signals leading to inflammation. These findings highlight esophageal allergy as a protease-mediated disease, suggesting that disarming of proteases by delivering protease inhibitors has the potential to be therapeutic in allergic disease. Read the publication now.