Integrating deep phenotyping and functional genomics to understand the mechanistic basis of primary lymphatic anomalies

整合深层表型分析和功能基因组学，了解原发性淋巴异常的机制基础

• 批准号: MR/Y013786/1
• 负责人: Pia Ostergaard
• 金额: $ 355.47万
• 依托单位: St George's, University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY013786%2F1
• 关键词: Integrating; deep; phenotyping; functional; genomics

The importance of the lymphatic circulation to human biology and health is hugely underestimated. A major reason for this is an absence of ways to investigate the lymphatics in humans. Veins on the back of the hand are easily seen, but the lymph vessels are invisible. Standard methods of analysing them such as x-ray, ultrasound, CT and MRI cannot easily detect the lymphatic vessels. Consequently, the lymphatic system has been largely underrated and its role in disease not widely appreciated.Through cellular and animal research we now know that the lymphatics play an important part in heart disease, cancer, infection, and fat metabolism; the four main challenges in healthcare today. Knowledge of how lymphatics do and do not work in humans has not kept pace, largely because of difficulties with investigation.While circulating blood is the main supply system for the body (providing water, nutrients, and oxygen to all cells), lymphatics are the returning, recycling and cleansing system. Lymphatic vessels are like veins but instead carry lymph fluid from tissues to lymph glands. The lymphatic system houses most of our immune cells such as lymphocytes. Infections, including Covid, must enter the lymph vessels and reach the lymph glands to activate lymphocytes. This develops effective immunity against that infection.The main consequence of a failure of lymphatic function is a condition called lymphoedema - where swelling occurs due to fluid accumulation, often in a limb and more commonly the legs. People with the condition also have reduced circulation of immune cells, which leads to an increased risk of infection that can be recurrent and life threatening. Lymphoedema is common (with 400,000 people in the UK, and 250 million people affected worldwide) but is not often diagnosed due to lack of awareness amongst clinicians. There are two different types - secondary lymphoedema (a result of damage to a previously healthy lymphatic system), and the much rarer primary lymphoedema (due to a genetic fault).Unlike cardiovascular disease and cancer, not one drug is licensed to treat lymphoedema and no universally successful surgical treatment exists. Thus, currently, lymphoedema cannot be cured and is managed through a range of physical therapies such as massage and compression to improve swelling.At St George's Hospital we operate a primary and paediatric lymphoedema clinic to which patients are referred from across the UK. More than 20 years of seeing patients with primary lymphoedema and lymphatic malformations, collectively known as primary lymphatic anomaly (PLA), has resulted in the discovery of several causal genes. Consequently, the St George's Hospital lymphoedema clinic is internationally renowned and has been appointed a Centre of Excellence, and has the largest collection of patients with lymphoedema anywhere in the world.The research proposed here is designed to improve our understanding of the mechanisms that lead to lymphoedema in humans through use of newly developed and more powerful investigatory methods. Patients with PLA - because of an inborn fault in lymphatic function caused by a gene mutation - will be studied so we can piece together how these faults are a driver of lymphoedema. This process has already begun in one type of PLA where the gene (PIK3CA) fault is not inherited but develops only in some cells and tissues of the body, a so-called somatic mosaic disorder. A drug now exists to block the effects of the faulty gene causing this lymphatic problem. Trials using this drug are now underway with St George's as one of a few centres for recruitment. Knowledge of other causal genes and the mechanisms producing the lymphoedema as planned in this research project, will create opportunities for new treatments. We believe the results of our work can be extended to other types of lymphoedema, such as those secondary to for example breast cancer treatment.

淋巴循环对人体生物学和健康的重要性被严重低估。一个主要的原因是缺乏研究人类遗传学的方法。手背上的静脉很容易看到，但淋巴管是看不见的。分析它们的标准方法，如X射线，超声波，CT和MRI不能轻易检测淋巴管。因此，淋巴系统在很大程度上被低估了，它在疾病中的作用也没有得到广泛的认识。通过细胞和动物研究，我们现在知道，淋巴系统在心脏病、癌症、感染和脂肪代谢中起着重要作用;这是当今医疗保健面临的四大挑战。由于研究的困难，对血液循环系统在人体内的作用和作用机制的了解还没有跟上。血液循环系统是人体的主要供应系统（为所有细胞提供水、营养和氧气），而血液循环系统则是返回、循环和清洁系统。淋巴管类似于静脉，但将淋巴液从组织运送到淋巴腺。淋巴系统容纳了我们大多数的免疫细胞，如淋巴细胞。包括新型冠状病毒在内的感染必须进入淋巴管并到达淋巴腺才能激活淋巴细胞。淋巴功能衰竭的主要后果是淋巴水肿--由于液体积聚而发生肿胀，通常发生在肢体，更常见的是腿部。患有这种疾病的人也会减少免疫细胞的循环，这会导致感染的风险增加，这种感染可能会复发并危及生命。脑水肿很常见（英国有40万人，全球有2.5亿人受影响），但由于临床医生缺乏意识，通常不会被诊断出来。有两种不同的类型-继发性淋巴水肿（由于先前健康的淋巴系统受损），以及更罕见的原发性淋巴水肿（由于遗传缺陷）。与心血管疾病和癌症不同，没有一种药物被许可用于治疗淋巴水肿，也没有普遍成功的手术治疗。因此，目前，淋巴水肿无法治愈，只能通过一系列物理疗法，如按摩和压迫来改善肿胀。在St乔治医院，我们经营着一家初级和儿科淋巴水肿诊所，患者来自英国各地。20多年来，我们对原发性淋巴水肿和淋巴畸形（统称为原发性淋巴异常（PLA））患者的观察发现了几个致病基因。因此，圣乔治医院淋巴水肿诊所是国际知名的，并已被任命为卓越中心，并有最大的收集淋巴水肿患者在世界任何地方。这里提出的研究旨在提高我们的理解，导致人类淋巴水肿的机制，通过使用新开发的和更强大的治疗方法。PLA患者--由于基因突变导致的淋巴功能先天缺陷--将被研究，这样我们就可以拼凑出这些缺陷是如何成为淋巴水肿的驱动因素的。这一过程已经在一种类型的PLA中开始，其中基因（PIK3CA）缺陷不是遗传的，而是仅在身体的一些细胞和组织中发展，即所谓的体细胞嵌合体疾病。现在有一种药物可以阻断导致淋巴问题的缺陷基因的作用。使用这种药物的试验正在进行中，圣乔治是少数几个招募中心之一。如本研究项目所计划的，对其他致病基因和产生淋巴水肿的机制的了解将为新的治疗方法创造机会。我们相信，我们的工作结果可以扩展到其他类型的淋巴水肿，例如继发于乳腺癌治疗的淋巴水肿。