DEMISTIFI Multi Morbidity: DEfining MechanIsms Shared across mulTI-organ FIbrotic disease to prevent the development of long term multi-morbidity

DEMISTIFI 多重发病率：确定多器官纤维化疾病共享的机制，以预防长期多重发病率的发展

• 批准号: MR/V005324/1
• 负责人: Gisli Jenkins
• 金额: $ 12.85万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV005324%2F1
• 关键词: DEMISTIFI; Multi; Morbidity; DEfining; MechanIsms

Scarring (fibrosis) affects every organ in the body and has been estimated to cause approximately one third of all deaths world-wide. Scarring classically affects the lungs and liver in response to environmental injury such as cigarette smoke, industrial dusts (eg asbestos) and alcohol. However, scarring also affects the heart and kidneys leading to heart and renal failure, the bone marrow leading to blood disease, the pancreas leading to diabetes, the blood vessels leading to strokes and heart attacks and the brain in multiple sclerosis and motor neurone disease. Multi-morbid fibrotic disease defines groups (clusters) of conditions that occur together and are characterised by scarring in various organs. Some are known such as short telomere syndromes leading to liver, lung and bone marrow scarring and connective tissue disease related scarring in muscle and joint disease. However, many scarring clusters are not well recognised (eg lung fibrosis and diabetes) and it is possible that there are completely unknown clusters that may reflect distinct genetic or environmental risk factors for scarring. Scarring is often progressive, notably in the lungs, liver and kidneys where it frequently leads to death or the need for organ transplantation. In some cases if the environmental trigger can be removed the scarring will stop, or even improve, but in other situations the scarring will progress regardless of whether the environmental cause is removed. This may reflect advanced disease which is 'beyond repair' or specific genetic interactions with the environmental triggers. The aim of this proposal is to understand how genetic and environmental risk factors interact to promote the development of progressive fibrosis across a number of different organs. These studies will address a focused question which will define which groups of scarring diseases are linked by genes that cause telomeres to shorten and cause premature ageing, and are known to be responsible for the known cluster of lung liver and bone marrow scarring. We will investigate the interaction between these genes and known environmental triggers including cigarette, alcohol and dusts as well as other triggers that may not yet have been identified. We will determine whether the biological pathways which are responsible for lung, liver or bone marrow fibrosis may also lead to scarring in other organs and whether they link expanded clusters of scarring involving the lung, liver, pancreas, kidney, bone marrow, brain, heart, gastrointestinal tract, or whether there are other genes that promote different clusters of scarring disease.We will then investigate whether medicines that are known to protect against certain fibrotic diseases within these clusters (for example metformin for diabetes and simvastatin for heart disease and stroke) might have beneficial affects across the full spectrum of fibrotic disease by targeting disease pathways that are shared across the different organs.These studies will require a collaboration between academics and clinicians with expertise in studying populations, genetics, cells, specific diseases, radiology, and 'big data' analysis to take a team science approach to solving a very important and challenging problem. The DEMISTIFI consortium will provide the expertise to deliver the evidence needed to understand multi organ scarring to improve treatment approaches that will help prevent this devastating scarring process throughout the body.

瘢痕形成(纤维化)影响到身体的每个器官，据估计，它导致的死亡约占全球死亡人数的三分之一。在香烟烟雾、工业粉尘(如石棉)和酒精等环境伤害下，疤痕通常会影响肺和肝脏。然而，疤痕也会影响心脏和肾脏，导致心脏和肾功能衰竭，骨髓导致血液疾病，胰腺导致糖尿病，血管导致中风和心脏病发作，以及多发性硬化症和运动神经元疾病的大脑。多发性纤维性疾病是指一组(群)共同发生的病症，其特征是在不同的器官形成疤痕。其中一些是已知的，如导致肝、肺和骨髓疤痕的短端粒综合征，以及肌肉和关节疾病中与结缔组织病相关的疤痕。然而，许多疤痕簇没有被很好地识别(例如肺纤维化和糖尿病)，并且可能有完全未知的簇可能反映了不同的遗传或环境因素对疤痕形成的风险。疤痕形成往往是进行性的，特别是在肺、肝和肾脏，它经常导致死亡或需要器官移植。在某些情况下，如果环境诱因可以移除，疤痕就会停止，甚至改善，但在其他情况下，无论环境原因是否被移除，疤痕都会继续形成。这可能反映了无法修复的晚期疾病，或者是特定的基因与环境因素的相互作用。这项建议的目的是了解遗传和环境风险因素如何相互作用，促进跨多个不同器官的进行性纤维化的发展。这些研究将解决一个重点问题，该问题将确定哪些组的疤痕疾病与导致端粒缩短并导致过早衰老的基因有关，并已知是导致肺、肝和骨髓疤痕形成的已知原因。我们将调查这些基因与已知的环境诱因之间的相互作用，包括香烟、酒精和粉尘，以及其他可能尚未确定的诱因。我们将确定导致肺、肝或骨髓纤维化的生物途径是否也会导致其他器官的疤痕形成，以及它们是否与肺、肝、胰腺、肾、骨髓、脑、心脏、胃肠道的疤痕扩大有关。或者是否有其他基因促进不同的瘢痕疾病簇。然后，我们将调查已知的预防这些簇中某些纤维化疾病的药物(例如用于糖尿病的二甲双胍和用于心脏病和中风的辛伐他汀)是否会通过靶向不同器官共享的疾病途径，对所有纤维化疾病产生有益影响。这些研究将需要在研究人口、遗传学、细胞、特定疾病、放射学和‘大数据’分析方面的学者和临床医生之间的合作，以团队科学的方法解决一个非常重要和具有挑战性的问题。DEMISTIFI财团将提供所需的专业知识，以提供了解多器官疤痕形成所需的证据，以改进治疗方法，帮助防止全身这种毁灭性的疤痕过程。

项目成果

Genetic overlap between idiopathic pulmonary fibrosis and COVID-19

特发性肺纤维化和 COVID-19 之间的基因重叠

• DOI: 10.1101/2021.12.08.21267459
• 发表时间: 2021
• 作者: Allen R

Beyond epithelial damage: vascular and endothelial contributions to idiopathic pulmonary fibrosis.

• DOI: 10.1172/jci172058
• 发表时间: 2023-09-15
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: May, James;Mitchell, Jane A.;Jenkins, R. Gisli
• 通讯作者: Jenkins, R. Gisli

Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity

特发性肺纤维化与 COVID-19 严重程度之间存在共同的遗传病因

• DOI: 10.1101/2020.12.15.20248279
• 发表时间: 2020
• 作者: Fadista J

Classifying the unclassifiable-a Delphi study to reach consensus on the fibrotic nature of diseases.

• DOI: 10.1093/qjmed/hcad050
• 发表时间: 2023-06-08
• 期刊: QJM-AN INTERNATIONAL JOURNAL OF MEDICINE
• 影响因子: 13.3
• 作者: Massen, G. M.;Allen, R. J.;Leavy, O. C.;Selby, N. M.;Aithal, G. P.;Oliver, N.;Parfrey, H.;Wain, L., V;Jenkins, G.;Stewart, I;Quint, J. K.
• 通讯作者: Quint, J. K.

Mapping brain endophenotypes associated with idiopathic pulmonary fibrosis genetic risk

绘制与特发性肺纤维化遗传风险相关的大脑内表型

• DOI: 10.1101/2022.03.25.22272932
• 发表时间: 2022
• 作者: Mohammadi-Nejad A