T-bet as a master regulator of mucosal immunity and inflammatory bowel disease.

炎症性肠病（IBD）影响了英国24万人，每年花费NHS 7亿英镑。它会导致残疾症状，生活质量受损和严重的并发症，包括癌症，肠梗阻和肠穿孔。许多患者将住院治疗，一些患者将需要接受毁容手术。不幸的是，它优先影响年轻的，经济上活跃的患者，他们一生都患有这种困难的疾病。IBD患者比未受影响的人失去更多的工作日，更有可能失业，其发病率似乎正在增加。目前，即使是最好的治疗策略也无法长时间控制疾病。IBD被认为是由肠道免疫系统的不适当激活引起的，这引发了肠道的慢性炎症。现在认识到，某些免疫细胞在IBD中起着启动和传播这种有害炎症过程的作用。近年来，我们在了解哪些免疫细胞类型和哪些免疫分子可能在疾病过程中发挥重要作用方面取得了相当大的进展。希望在未来几年内，对肠道免疫细胞调节的见解可以被利用来为更好的治疗方法的开发提供信息。该提案旨在确定与IBD相关的免疫异常是否可以特异性靶向预防疾病。它专注于一种称为转录因子的分子，这是IBD患者肠道免疫反应的重要调节因子。其中一种分子（T-bet）是肠道免疫细胞的潜在重要调节因子。它在IBD患者和发生类似IBD的肠道炎症的小鼠中异常表达。据预测，它控制许多不同的免疫机制，包括一些被认为是重要的IBD病因。T-bet仅存在于免疫细胞和其他骨髓来源的细胞中。因此，可以预见，调节其在患者体内的作用不太可能在身体的其他器官中引起意想不到的副作用。通过比较正常小鼠与某些免疫细胞类型中缺乏T-bet的小鼠，我们将确定这种特定分子如何影响肠道中的免疫特异性机制并影响IBD易感性。我们还将尝试确定新的治疗靶点，这些靶点旨在选择性抑制导致IBD的细胞类型。这将提供关于靶向T-bet是否可能逆转IBD炎症的见解，这是患有这种致残性疾病的患者非常希望的目标。这项研究将在伦敦国王学院由在IBD研究方面有良好记录的科学家和医生进行。此外，还与伦敦玛丽女王大学、伦敦大学学院和曼彻斯特大学的其他专家研究人员建立了密切合作，以最大限度地利用专业知识。玛丽女王大学、伦敦大学学院和曼彻斯特大学的其他专家研究人员。

Inflammatory bowel disease (IBD) affects 240,000 people in the UK and costs the NHS £700 million every year. It causes disabling symptoms, impaired quality of life and serious complications including cancer, bowel blockage and bowel perforation. Many patients will be hospitalised and some will need to undergo disfiguring operations. Unfortunately, it preferentially affects young, economically active patients whom live with this difficult disease for life. IBD patients lose more working days and are more likely to be unemployed than unaffected people and its incidence appears to be increasing. At present, even the best treatment strategies fail to keep the disease in check for long periods of time. It is thought that IBD is caused by inappropriate activation of the intestinal immune system, which triggers chronic inflammation of the gut. It is now appreciated that certain immune cells play an instrumental role initiating and propagating this detrimental inflammatory process in IBD. In recent years there have been considerable advances made in our understanding of which immune cell types and which immune molecules are likely to play important roles in the disease process. It is hoped that in the coming years that insights into the regulation of gut immune cells can be harnessed to inform the development of better treatments.This proposal aims to determine whether the immune abnormalities associated with IBD can be specifically targeted to prevent the disease. It focuses on a type of molecule known as a transcription factor, which is a very important regulator of the immune responses seen in the gut of IBD patients.One of these molecules, (T-bet) stands out as a potentially important regulator of gut immune cells. It is abnormally expressed in IBD patients and in mice developing gut inflammation that resembles IBD. It is predicted to control many different immune mechanisms, including some of those thought to be important in IBD causation. T-bet is only found in immune cells and other bone marrow derived cells. It is therefore anticipated that modulating its action in patients is unlikely to cause unanticipated side effects in other organs of the body.By comparing normal mice with mice lacking T-bet in certain immune cell types we will determine how this particular molecule affects immune specific mechanisms in the gut and influences IBD susceptibility. We will also try to identify novel targets for therapies that are designed to selectively suppress affect the type of cells causing IBD. This will provide insight as to whether targeting T-bet is likely to reverse inflammation in IBD, a highly desirable goal for patients with this disabling disease.This research will be conducted at King's College London by scientists and doctors with proven track records in IBD research. In addition, close collaborations have been formed with other expert researchers at Queen Mary University of London, University College London and the University of Manchester in order to maximise expertise.