A functional dissection of the serotonin system in liver disease

肝脏疾病中血清素系统的功能剖析

• 批准号: G0700890/1
• 负责人: Derek Mann
• 金额: $ 38.48万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0700890%2F1
• 关键词: functional; dissection; serotonin; system; liver

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.

肝病正在威胁生命（英国10,000人死亡），并影响各行各业的人们，包括非常年幼的孩子，成年人应该是他们的生命和老年人。肝病不仅是生活方式差的结果（酒精，饮食不良，缺乏运动等）的结果，而且还由通过输血，自身免疫性疾病和遗传性疾病传播的病毒引起。常见的最终结果是，肝脏会遭受逐渐疤痕的形成和正常功能性肝组织的丧失。 Mann教授和他的团队发现，一个称为5-羟色胺或5-HT的化学信使是患病肝脏中疤痕形成的调节器。 5-HT的活性由称为SERT的转运分子调节，该分子使细胞能够存储化学物质和5-HT受体在肝脏的疤痕细胞的表面上发现的5-HT受体。当受体结合5-HT时，他们对疤痕形成细胞进行编程以繁殖并制成刺激疤痕产生的蛋白质。这是一个令人兴奋的发现，因为已经开发出许多靶向SERT和5-HT受体的药物，这些药物用于治疗抑郁症和胃肠道疾病。确实，作为该赠款应用的试验数据，曼恩教授已经发现5-HT受体的拮抗剂抑制了疤痕形成细胞的活性。本应用中提出的项目将仔细剖析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形成疤痕并刺激肝脏的正常再生性质。