Pathomolecular mechanisms of intracerebral haemorrhage: functional analysis of collagen IV variants.

脑出血的病理分子机制：IV 型胶原蛋白变体的功能分析。

• 批准号: MR/R005567/1
• 负责人: Tom Van Agtmael
• 金额: $ 89.94万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR005567%2F1
• 关键词: Pathomolecular; mechanisms; intracerebral; haemorrhage; functional

Each year, 150,000 people in the UK have a stroke, which is a major cause of death and disability. There are two types of stroke: those caused by blocked blood vessels and those due to rupture of blood vessels resulting in a brain bleed (haemorrhagic stroke). Intracerebral haemorrhage (brain bleeding), accounts for 15% of all adult strokes, carries the worst prognosis and there are no specific treatments for intracerebral haemorrhage, in part because we do not understand the causes of this disease.The "basement membrane" is a structure that forms outside of cells and provides strength to blood vessels by acting as a permanent scaffold in the walls of blood vessels. Two collagen proteins produced from genes named COL4A1 and COL4A2 are major components of this basement membrane. We have found that defects in these genes, called "mutations," cause rare inherited forms of haemorrhagic stroke that affects multiple people within a family. Collagen is produced and folded inside cells and then moved out of cells. Our work suggests that these rare mutations affect basement membrane integrity but also have their damaging effects by causing incorrect folding of the COL4A1 and COL4A2 proteins. These misfolded collagen proteins then accumulate inside cells and causes these cells to become "stressed", which interferes with their function.Excitingly, our new data suggest that changes in these collagen genes, which occur frequently in the population, are a risk factor for intracerebral haemorrhage in the general population. This raises several important questions: 1) How many stroke patients are affected by these common gene changes? 2) How do the changes that occur in the general population cause bleeding, and does their mechanism involve the accumulation of protein within cells and cell stress, similar to the rare inherited mutations?To answer these questions we will analyse the COL4A1 and COL4A2 genes in DNA samples from a large number of patients from the general population that have had an intracerebral haemorrhage. By identifying the changes that occur in these genes we will determine the proportion of patients in whom altered collagen IV genes contribute to stroke. We will use computer analysis to predict whether the identified alterations affect the amount of collagen produced or may lead to changes in protein structure, similar to what occurs with mutations in the rare inherited forms of intracerebral haemorrhage. For some of the changes identified, we will then directly determine whether they lead to accumulation of collagen and "stress" inside blood vessel cells and establish their effects on the composition of the basement membrane. We will then investigate how the cell stress and basement membrane defects affect the health and function of these cells. Finally, we will determine if this cell stress response, basement membrane defects and other identified defects from blood vessels cells occur in brain samples. By combining DNA analysis with investigations in cells and brains, we will obtain a much better understanding of how intracerebral haemorrhage develops. This will aid in the long term the development of new and/or more effective therapies for intracerebral haemorrhaging. By identifying the proportion of intracerebral haemorrhage patients in which these collagen changes occur and determining if all changes act in the same way, our results can indicate if a future "one version fits all" therapy is likely to be feasible and we will learn for how many patients these treatments may be effective. Interestingly, some drugs that are used to treat other diseases can reduce stress in cells grown in the laboratory, which would allow relative rapid progress to be made in developing treatments for stroke.

每年，英国有15万人中风，这是死亡和残疾的主要原因。中风有两种类型：由血管阻塞引起的中风和由血管破裂导致脑出血（出血性中风）引起的中风。脑出血（脑出血），占所有成人中风的15%，预后最差，并且没有针对脑出血的特定治疗方法，部分原因是我们不了解这种疾病的原因。“基底膜”是一种在细胞外形成的结构，通过充当血管壁中的永久支架为血管提供强度。由名为COL 4A 1和COL 4A 2的基因产生的两种胶原蛋白是这种基底膜的主要成分。我们发现，这些基因的缺陷，称为“突变”，会导致罕见的遗传性出血性中风，影响一个家庭中的多个人。胶原蛋白在细胞内产生并折叠，然后移出细胞。我们的工作表明，这些罕见的突变会影响基底膜的完整性，但也会通过导致COL 4A 1和COL 4A 2蛋白的不正确折叠而产生破坏性影响。这些错误折叠的胶原蛋白然后在细胞内积累，并导致这些细胞变得“应激”，这干扰了它们的功能。令人兴奋的是，我们的新数据表明，这些胶原基因的变化，在人群中经常发生，是一般人群中脑出血的危险因素。这就提出了几个重要的问题：1）有多少中风患者受到这些常见基因变化的影响？2)一般人群中发生的变化如何导致出血，其机制是否涉及细胞内蛋白质的积累和细胞应激，类似于罕见的遗传突变？为了回答这些问题，我们将分析大量脑出血患者的DNA样本中的COL 4A 1和COL 4A 2基因。通过识别这些基因的变化，我们将确定IV型胶原基因改变导致中风的患者比例。我们将使用计算机分析来预测所识别的改变是否会影响胶原蛋白的产生量或可能导致蛋白质结构的变化，类似于罕见的遗传性脑出血中的突变。对于一些确定的变化，我们将直接确定它们是否会导致血管细胞内胶原蛋白的积累和“压力”，并确定它们对基底膜组成的影响。然后，我们将研究细胞应激和基底膜缺陷如何影响这些细胞的健康和功能。最后，我们将确定这种细胞应激反应、基底膜缺陷和其他来自血管细胞的识别缺陷是否发生在大脑样本中。通过将DNA分析与细胞和大脑的研究相结合，我们将更好地了解脑出血是如何发展的。这将有助于长期开发新的和/或更有效的脑出血治疗方法。通过确定发生这些胶原蛋白变化的脑出血患者的比例，并确定所有变化是否以相同的方式起作用，我们的结果可以表明未来的“一个版本适合所有”治疗是否可行，我们将了解这些治疗对多少患者有效。有趣的是，一些用于治疗其他疾病的药物可以减少实验室中生长的细胞的压力，这将使开发中风治疗方法取得相对快速的进展。

项目成果

The role of basement membranes in cardiac biology and disease.

• DOI: 10.1042/bsr20204185
• 发表时间: 2021-08-27
• 期刊: Bioscience reports
• 影响因子: 4
• 作者: Boland E;Quondamatteo F;Van Agtmael T
• 通讯作者: Van Agtmael T

Small vessels, dementia and chronic diseases - molecular mechanisms and pathophysiology.

• DOI: 10.1042/cs20171620
• 发表时间: 2018-04-30
• 期刊: Clinical science (London, England : 1979)
• 作者: Horsburgh K;Wardlaw JM;van Agtmael T;Allan SM;Ashford MLJ;Bath PM;Brown R;Berwick J;Cader MZ;Carare RO;Davis JB;Duncombe J;Farr TD;Fowler JH;Goense J;Granata A;Hall CN;Hainsworth AH;Harvey A;Hawkes CA;Joutel A;Kalaria RN;Kehoe PG;Lawrence CB;Lockhart A;Love S;Macleod MR;Macrae IM;Markus HS;McCabe C;McColl BW;Meakin PJ;Miller A;Nedergaard M;O'Sullivan M;Quinn TJ;Rajani R;Saksida LM;Smith C;Smith KJ;Touyz RM;Trueman RC;Wang T;Williams A;Williams SCR;Work LM
• 通讯作者: Work LM

Vascular Collagen Type-IV in Hypertension and Cerebral Small Vessel Disease.

• DOI: 10.1161/strokeaha.122.037761
• 发表时间: 2022-12
• 期刊: Stroke
• 影响因子: 8.3

A novel human iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases.

• DOI: 10.1016/j.stemcr.2023.10.014
• 发表时间: 2023-12-12
• 期刊: STEM CELL REPORTS
• 影响因子: 5.9
• 作者: Al-Thani, Maha;Goodwin-Trotman, Mary;Bell, Steven;Patel, Krushangi;Fleming, Lauren K.;Vilain, Catheline;Abramowicz, Marc;Allan, Stuart M.;Wang, Tao;Cader, M. Zameel;Horsburgh, Karen;Van Agtmael, Tom;Sinha, Sanjay;Markus, Hugh S.;Granata, Alessandra
• 通讯作者: Granata, Alessandra

Material-driven fibronectin assembly rescues matrix defects due to mutations in collagen IV in fibroblasts.

• DOI: 10.1016/j.biomaterials.2020.120090
• 发表时间: 2020-09
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Ngandu Mpoyi E;Cantini M;Sin YY;Fleming L;Zhou DW;Costell M;Lu Y;Kadler K;García AJ;Van Agtmael T;Salmeron-Sanchez M
• 通讯作者: Salmeron-Sanchez M