A functional dissection of the serotonin system in liver disease

Liver disease is life threatening (10,000 deaths/annum in the UK) and impacts on people from all walks of life including very young children, adults at what should be their prime of life and the elderly. Liver disease is not only the result of poor life style choices (alcohol, poor diet, lack of exercise etc) but is also caused by viruses transmitted via blood transfusions, by autoimmune diseases and by hereditary conditions. The common end result is that the liver suffers from progressive scar formation and loss of normal functional liver tissue. Prof Mann and his team have discovered that a chemical messenger called serotonin or 5-HT is a regulator of scar formation in the diseased liver. The activity of 5-HT is regulated by a transport molecule called SERT that enables cells to store the chemical and by 5-HT receptors found on the surface of the scar-forming cells of the liver. When the receptors bind 5-HT they programme the scar-forming cell to multiply and make proteins that stimulate scar production. This is an exciting discovery since there are already many drugs developed that target SERT and 5-HT receptors which are used to treat depression and gastrointestinal conditions. Indeed, as pilot data for this grant application, Prof Mann has already discovered that antagonists of 5-HT receptors dampen down the activity of scar-forming cells. The project proposed in this application will carefully dissect the functions of SERT and 5-HT receptors and determine if drugs that modify their activity can prevent scar formation and stimulate the normal regenerative properties of the liver.

Prof Mann and his team carry out research that has the long-term goal of generating new therapies that prevent and even reverse scaring (fibrosis) of the liver. In this project they will determine if the hepatic serotonin (5-HT) system can be exploited to prevent fibrosis and promote optimal liver regeneration. The basis for the project is the recent discoveries that 5-HT promotes hepatocyte regeneration but also stimulates the fibrogenic properties of hepatic myofibroblasts (HM). If Mann can identify pharmaceutical modifiers of the 5-HT system that promote regeneration while suppressing fibrosis then there will be rapid progress of these drugs to the clinic. This requires a detailed functional dissection of the key regulatory components of the 5-HT system in the diseased liver and as controllers of HM fate and function. Further experimental background is Mann s novel and exciting discovery that HM express 5-HT transporters (SERT) and several members of the 5-HT receptor family. SERT may enable HM to provide a local supply of 5-HT to promote hepatocyte regeneration in response to local tissue damage. However, release of 5-HT also promotes HM proliferation, inhibits apoptosis and stimulates fibrogenic gene expression via binding to 5-HT receptors on the surface of HM. Mann has described how 5-HT receptor antagonists inhibit these fibrogenic properties of 5-HT. There is now a need to determine precisely which members of the highly complex 5-HT receptor family are the best targets for achieving repression of fibrosis. This will be carried out using human and rodent HM, in vivo models of liver disease and application of receptor selective antagonists in combination with siRNA technology. Mann will also investigate if SERT can modulate fibrosis and regeneration by determining the response of SERT gene knockout mice to chronic liver injury. The anticipated outcome will be the identification of one or more pharmacologically well characterised attenuators of the 5-HT system that can suppress fibrosis and optimises normal hepatocyte regeneration. Of note, a pharmaceutical partner (EPIX pharmaceuticals inc) has already expressed keen interest to Prof Mann in developing 5-HT receptor antagonists as therapeutics in the liver clinic.