Grant: Project Grant

Hepcidin is a hormone that is produced in the liver and circulates in the blood. Although hepcidin has numerous physiological roles (and has antibacterial properties), it is mostly known as the major regulator of iron levels in the body. Interestingly, diseases such as beta-thalassemia, hemochromatosis, liver fibrosis and liver cirrhosis have been associated with low levels of circulating hepcidin suggesting that hepcidin itself might have a direct role in these diseases. Therefore, it is logical to assume that elevating hepcidin levels could be beneficial in these conditions. Our group has been focusing on an enzyme called matriptase-2 (also known as TMPRSS6), which is found only in liver and which controls hepcidin production. Our project begins by initially focusing on our findings that the human liver expresses four distinct forms of TMPRSS6. Some of the forms are enzymatically active, some are not but how one form is expressed in comparison to other forms remains unclear. Our proposal will study the different forms of TMPRSS6 found in liver, will focus on their functionality and the consequence of the presence of these different isoforms on the production of hepcidin. Conversely, we also propose two different approaches to reduce the enzymatic activity of TMPRSS6 thereby increasing hepcidin levels. One of these involves the synthesis of small molecule inhibitors to abolish the enzymatic activity of the enzyme. Another is a completely novel pharmacological approach based on the use of small sequences of DNA to control which TMPRSS6 isoform is expressed. Knowing that certain isoforms are enzymatically inactive, this 'switch' of expression could have profound effects on the production of hepcidin. Therefore, our studies are meant to shed light into the role of TMPRSS6 in hepcidin production and to propose novel ways at increasing hepcidin levels in hepcidin-deficiency disorders.