MICA - DEfining MechanIsms Shared across mulTI-organ FIbrosis to prevent the development of long-term multi-morbidity DEMISTIFI-Multi Morbidity

MICA - 多器官纤维化共享的定义机制，以防止长期多重发病的发展 DEMISTIFI-Multi Morbidity

• 批准号: MR/W014491/1
• 负责人: Gisli Jenkins
• 金额: $ 363.94万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW014491%2F1
• 关键词: MICA; DEfining; MechanIsms; Shared; across

Amended lay summary: Scarring ("fibrosis") of the internal organs occurs in many common diseases, including diabetes (scarring in the pancreas), high blood pressure (blood vessels), chronic kidney disease (kidney), cirrhosis (liver) and pulmonary fibrosis (lungs). Scarring of the internal organs can stop these organs working properly and causes about one third of all deaths world-wide. People can be affected by scarring in more than one organ.Factors believed to contribute to scarring include smoking, alcohol, obesity and infections such as COVID-19. These external factors are known as "environmental" factors. There are also a number of genetic factors (known as genetic mutations or 'variants') that can run in families with people affected more likely to have scarring in different organs, at a younger age.Genetic factors that cause scarring are often seen in short telomere syndrome, a form of accelerated aging, which leads to scarring throughout the body. In severe cases, this can start in childhood, with scarring affecting different parts of the body. It often starts with the bone marrow, causing severe anaemia, infections and bleeding, and later in the liver leading to cirrhosis or the lung leading to death. Other people could have milder genetic problems that they may not know about. These might be quite common and cause scarring only in old age or if triggered by external (environmental) factors such as smoking, obesity or drinking too much alcohol. It is likely that both genetic and environmental/external risk factors cause scarring of different organs and may happen at different times. If patterns of scarring can be identified when young, development of more extensive scarring, in multiple organs in later life, could be prevented. This could be done by identifying groups of people at risk of scarring and working out which specific treatments or medications will work best for each group. Having identified these groups of people, targeted therapies would be used to encourage people to change their lifestyle or to take the medicines that are most likely to be effective for each particular person. The aim of our research is to identify patterns of scarring in different organs, which we have termed Fibrotic Multi-Morbidity (FMM). We will use new technology such as Magnetic Resonance Imaging (MRI) scans to measure the extent of scarring in different organs, in order to generate a "Fibrotic Multi-Morbidity" Score (i.e., to measure the severity of the scarring). This will enable us to ascertain the full extent of scarring, provide an early warning and detect the spread of scarring from one organ to another. We will map the genetic and environmental/external triggers of scarring in different organs and investigate the underlying biological causes of the scarring so that we can find the treatments to prevent or cure it. We suspect that many medications that are already in use could help prevent or treat scarring but before we can recommend them, we need to prove that these medicines work.In this way, we hope to provide the right treatment to the right person to stop scarring from destroying the organ in which it is found and to prevent it spreading to other organs. These treatments could involve lifestyle changes, such as weight loss and exercise, and/or medications. We hope that by treating and preventing scarring- 'fibrosis', we may be able to help a lot of people stay healthy and live longer, healthier lives.

修订的奠定总结：内脏器官的瘢痕形成（“纤维化”）发生在许多常见疾病中，包括糖尿病（胰腺中的瘢痕形成）、高血压（血管）、慢性肾病（肾脏）、肝硬化（肝脏）和肺纤维化（肺）。内部器官的疤痕可以阻止这些器官正常工作，并导致全球约三分之一的死亡。人们可能会受到不止一个器官瘢痕的影响。据信导致瘢痕形成的因素包括吸烟、酒精、肥胖和COVID-19等感染。这些外部因素被称为“环境”因素。还有一些遗传因素（称为基因突变或“变异体”）可以在家庭中运行，受影响的人更容易在不同器官中留下疤痕，在年轻的时候。导致疤痕的遗传因素通常见于短端粒综合征，这是一种加速衰老的形式，会导致全身疤痕。在严重的情况下，这可能始于童年，疤痕影响身体的不同部位。它通常从骨髓开始，引起严重的贫血，感染和出血，后来在肝脏导致肝硬化或肺部导致死亡。其他人可能有轻微的遗传问题，他们可能不知道。这些可能很常见，只有在老年或由外部（环境）因素如吸烟，肥胖或饮酒过多引发时才会导致疤痕。遗传和环境/外部风险因素可能会导致不同器官的瘢痕形成，并且可能发生在不同的时间。如果在年轻时就能识别出疤痕形成的模式，那么在以后的生活中，在多个器官中形成更广泛的疤痕就可以预防。这可以通过确定有疤痕风险的人群，并确定哪些特定的治疗或药物对每个群体最有效来实现。在确定了这些人群之后，将使用有针对性的治疗来鼓励人们改变生活方式或服用最有可能对每个特定人有效的药物。我们研究的目的是确定不同器官的瘢痕形成模式，我们称之为纤维化多发性硬化（FMM）。我们将使用诸如磁共振成像（MRI）扫描的新技术来测量不同器官中瘢痕形成的程度，以便生成“纤维化多发病”评分（即，以测量疤痕的严重性）。这将使我们能够确定疤痕的全部范围，提供早期预警，并发现疤痕从一个器官蔓延到另一个器官。我们将绘制不同器官中瘢痕形成的遗传和环境/外部触发因素，并调查瘢痕形成的潜在生物学原因，以便我们能够找到预防或治疗瘢痕形成的治疗方法。我们怀疑许多已经使用的药物可以帮助预防或治疗瘢痕形成，但在我们推荐它们之前，我们需要证明这些药物有效。这样，我们希望为正确的人提供正确的治疗，以防止疤痕破坏发现疤痕的器官，并防止疤痕扩散到其他器官。这些治疗可能涉及生活方式的改变，如减肥和运动，和/或药物。我们希望通过治疗和预防疤痕-“纤维化”，我们可以帮助很多人保持健康，活得更长，更健康的生活。

项目成果

Using genetic information to define idiopathic pulmonary fibrosis in UK Biobank

英国生物银行利用遗传信息定义特发性肺纤维化

• DOI: 10.1101/2022.04.01.22273306
• 发表时间: 2022
• 作者: Leavy O

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

Assessing Causal Relationships Between Diabetes Mellitus and Idiopathic Pulmonary Fibrosis

• DOI: 10.1101/2024.01.04.24300827
• 发表时间: 2024-01
• 作者: Samuel Moss;Cosetta Minelli;O. Leavy;R. Allen;Nick Oliver;L. Wain;Gisli Jenkins;Iain Stewart;Mr. Samuel Moss;Margaret Turner Warwick

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.

Response to: Consensus and agreements on the classification of fibrotic diseases

回应：关于纤维化疾病分类的共识和协议

• DOI: 10.1093/qjmed/hcad120
• 发表时间: 2023
• 期刊: An International Journal of Medicine
• 作者: Massen G