Elucidating the role of GCN2 in the pathogenesis of pulmonary vascular disease

阐明GCN2在肺血管疾病发病机制中的作用

• 批准号: MR/R008051/1
• 负责人: Elaine Soon
• 金额: $ 133.47万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Fellowship
• 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%2FR008051%2F1
• 关键词: Elucidating; role; GCN2; pathogenesis; pulmonary

Pulmonary hypertension is a term that describes a group of diseases which have in common the following feature: increased blood pressure levels in the blood vessels leading into and out of the lungs, which leads to heart failure and finally death, if left untreated. There are two main types of pulmonary hypertension. In the first type, the obstruction is at the level of the arteries feeding the lungs ('pulmonary arterial hypertension') and in the second type the obstruction occurs either at or below the level of the veins draining the lungs ('pulmonary venous hypertension'). Recently there has been a discovery of a new inherited problem which can cause a rare form of pulmonary hypertension, pulmonary veno-occlusive disease (PVOD), which combines both arterial and venous features. This problem consists of mutations in the gene for a protein called general control nonderepressible 2, or GCN2. The GCN2 protein is crucially important in a reaction known as the integrated stress response, which is usually activated in periods of protein starvation. There has been no previous hint that problems with this protein can affect the heart or lung circulation; so this is a completely new area of research. Inherited pulmonary arterial hypertension has previously been linked with problems in another gene which creates a protein known as bone morphogenetic protein receptor type II (BMPR2). Patients with this problem have a deficiency of BMPR2. Finding this genetic problem has led to new ways to treat pulmonary arterial hypertension such as increasing BMPR2 levels or by activating the remaining BMPR2. These are currently being tested in mice. It is our hope that the discovery of GCN2 will drive the same process for pulmonary veno-occlusive disease specifically and pulmonary hypertension in general. Currently there is no specific treatment for either PVOD or pulmonary venous hypertension other than a transplant, which very few patients are eligible for. I plan to examine how exactly GCN2 deficiency affects the heart and lungs. To do this, we will use several models of the disease, such as fruit flies and mice lacking the GCN2 gene, and blood samples and lung blood vessel cells by patients with GCN2 mutations donated at the time of transplant. We will initially compare mice that are completely lacking this gene with normal mice and see whether GCN2-deficient mice develop pulmonary hypertension. If they don't, we will see whether crossing these mice with mice lacking BMPR2 will 'uncover' the disease. So far we have discovered that GCN2-deficient mice develop mild pulmonary hypertension and this is further exacerbated by adding in BMPR-2 deficiency. Our next steps are to see whether GCN2 is a protective factor and if replacing and or activating GCN2 will be protective against pulmonary hypertension in miceWe also know from the fly studies that the GCN2 and BMPR2 pathways overlap. For example, activating the GCN2 pathway reduces the reaction to stimulation of BMPR2 in fly wings and in fly cells. I will examine if this is also true in cells taken from human lung blood vessels. If BMPR2 is downstream of GCN2-related pathways then perhaps activating BMPR2 will be an alternative way of treating pulmonary hypertension associated with GCN2 deficiency. Once we understand how GCN2 deficiency leads to development of pulmonary hypertension in mice, we will check if these theories are supported in experiments using blood and tissue samples donated by pulmonary hypertension patients. Eventually we aim to develop new treatments for GCN2-associated pulmonary hypertension and to test them in clinical trials in patients.

肺动脉高压是描述一组疾病的术语，这些疾病共同具有以下功能：导致进出肺的血管中的血压水平升高，如果不治疗，这会导致心力衰竭并最终死亡。有两种主要类型的肺动脉高压。在第一种类型中，阻塞发生在为肺供血的动脉水平（“肺动脉高压”），而在第二种类型中，阻塞发生在为肺引流的静脉水平或低于该水平（“肺静脉高压”）。最近发现了一种新的遗传性问题，它可以引起一种罕见的肺动脉高压，肺静脉闭塞性疾病（PVOD），它结合了动脉和静脉的特点。这个问题是由一种蛋白质基因的突变引起的，这种蛋白质被称为一般控制非抑制蛋白2（GCN 2）。GCN 2蛋白在被称为综合应激反应的反应中至关重要，该反应通常在蛋白质饥饿期间被激活。以前没有迹象表明这种蛋白质的问题会影响心脏或肺循环;所以这是一个全新的研究领域。遗传性肺动脉高压以前与另一个基因的问题有关，该基因产生一种称为骨形态发生蛋白受体II型（BMPR 2）的蛋白质。患有这种疾病的患者缺乏BMPR 2。发现这种遗传问题导致了治疗肺动脉高压的新方法，例如增加BMPR 2水平或激活剩余的BMPR 2。目前正在小鼠中进行测试。我们希望GCN 2的发现将推动肺静脉闭塞性疾病和肺动脉高压的相同过程。目前，除了移植之外，没有针对PVOD或肺静脉高压的特异性治疗，很少有患者符合条件。我计划研究GCN 2缺乏症究竟如何影响心脏和肺。为此，我们将使用几种疾病模型，如缺乏GCN 2基因的果蝇和小鼠，以及移植时捐赠的GCN 2突变患者的血液样本和肺血管细胞。我们首先将完全缺乏这种基因的小鼠与正常小鼠进行比较，看看GCN 2缺陷小鼠是否会发生肺动脉高压。如果他们不这样做，我们将看看将这些小鼠与缺乏BMPR 2的小鼠杂交是否会“发现”这种疾病。到目前为止，我们已经发现GCN-2缺陷小鼠会出现轻度肺动脉高压，而BMPR-2缺陷会进一步加剧这种情况。我们的下一步是看看GCN 2是否是一个保护因子，以及替换和/或激活GCN 2是否会对小鼠的肺动脉高压产生保护作用。我们还从果蝇研究中得知，GCN 2和BMPR 2通路重叠。例如，激活GCN 2途径降低了对苍蝇翅膀和苍蝇细胞中BMPR 2刺激的反应。我将研究从人肺血管中提取的细胞是否也是如此。如果BMPR 2是GCN 2相关通路的下游，那么激活BMPR 2可能是治疗与GCN 2缺乏相关的肺动脉高压的另一种方法。一旦我们了解了GCN 2缺乏如何导致小鼠肺动脉高压的发展，我们将使用肺动脉高压患者捐赠的血液和组织样本来检查这些理论是否得到实验的支持。最终，我们的目标是开发GCN 2相关肺动脉高压的新疗法，并在患者的临床试验中进行测试。

项目成果

S70 Effectiveness of different parameters at admission as prognostic markers for mortality due to SARS-CoV-2: a 2-centre experience in UK and Spain

S70 入院时不同参数作为 SARS-CoV-2 死亡率预后标志物的有效性：英国和西班牙的 2 中心经验

• DOI: 10.1136/thorax-2021-btsabstracts.76
• 发表时间: 2021
• 作者: Shuvo M

S91 Patterns of cytokines and growth factors in pulmonary arterial hypertension patients with BMPR2 mutations and PAH patients without driving mutations and their influence on survival

S91 BMPR2突变肺动脉高压患者和无驱动突变PAH患者细胞因子和生长因子的模式及其对生存的影响

• DOI: 10.1136/thorax-2020-btsabstracts.96
• 发表时间: 2021
• 作者: Schwiening M

Different Cytokine Patterns in BMPR2-Mutation-Positive Patients and Patients With Pulmonary Arterial Hypertension Without Mutations and Their Influence on Survival.

• DOI: 10.1016/j.chest.2022.01.019
• 发表时间: 2022-06
• 期刊: CHEST
• 影响因子: 9.6
• 作者: Schwiening, Max;Swietlik, Emilia M.;Pandya, Divya;Burling, Keith;Barker, Peter;Feng, Oliver Y.;Treacy, Carmen M.;Abreu, Susana;Wort, S. John;Pepke-Zaba, Joanna;Graf, Stefan;Marciniak, Stefan J.;Morrell, Nicholas W.;Soon, Elaine
• 通讯作者: Soon, Elaine

Hematopoietic stem cell transplantation alters susceptibility to pulmonary hypertension in Bmpr2-deficient mice.

• DOI: 10.1177/2045894018801642
• 发表时间: 2018-10
• 期刊: Pulmonary circulation
• 影响因子: 2.6
• 作者: Crosby A;Toshner MR;Southwood MR;Soon E;Dunmore BJ;Groves E;Moore S;Wright P;Ottersbach K;Bennett C;Guerrero J;Ghevaert C;Morrell NW
• 通讯作者: Morrell NW

Elucidating how mutations in EIF2AK4 cause pulmonary vascular disease

阐明 EIF2AK4 突变如何导致肺血管疾病

• DOI: 10.17863/cam.106526
• 发表时间: 2024
• 作者: Schwiening M