A functional dissection of the serotonin system in liver disease

肝病是危及生命的（在英国每年有10,000人死亡），影响着各行各业的人，包括非常年幼的儿童、应该处于壮年期的成年人和老年人。肝病不仅是不良生活方式（酒精、不良饮食、缺乏锻炼等）的结果，也是由输血传播的病毒、自身免疫性疾病和遗传性疾病引起的。常见的最终结果是肝脏遭受进行性瘢痕形成和正常功能肝组织的丧失。曼恩教授和他的团队发现，一种叫做血清素或5-羟色胺的化学信使是患病肝脏中疤痕形成的调节剂。5-羟色胺的活性是由一种叫做SERT的转运分子调节的，SERT使细胞能够储存这种化学物质，而5-羟色胺受体则在肝脏形成疤痕的细胞表面发现。当受体与5-羟色胺结合时，它们会对形成疤痕的细胞进行编程，使其繁殖并产生刺激疤痕产生的蛋白质。这是一个令人兴奋的发现，因为已经有许多针对SERT和5-HT受体的药物被开发出来，用于治疗抑郁症和胃肠道疾病。事实上，作为这项拨款申请的试点数据，曼恩教授已经发现5-羟色胺受体拮抗剂可以抑制疤痕形成细胞的活性。本申请中提出的项目将仔细解剖SERT和5-HT受体的功能，并确定改变其活性的药物是否可以防止疤痕形成并刺激肝脏的正常再生特性。

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.