MRC Transition Support Award: Elucidating the role of GCN2 in the pathogenesis of pulmonary vascular disease

MRC 过渡支持奖：阐明 GCN2 在肺血管疾病发病机制中的作用

• 批准号: MR/W029251/1
• 负责人: Elaine Soon
• 金额: $ 50.29万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW029251%2F1
• 关键词: MRC; Transition; Support; Award; Elucidating

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 venoocclusive 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.We have made progress in trying to find out how and why loss of GCN2 leads to pulmonary hypertension - we have shown that mice lacking this gene also develop mild pulmonary hypertension, and that they also have markers in inflammation in their lungs and blood when they are older (5-6 months). However, giving GCN2-deficient cell models an inflammatory stimulus has not provoked a more severe response. Neither do the mice when they are given inflammatory stimuli at a younger age.Therefore we hypothesize that age is a contributing fact to the GCN2-associated pulmonary vascular phenotype. We are testing this by suimultaneously comparing all the cells from an untreated 8-week wild-type mouse lung to an untreated 8-week gcn2-deficient mouse lung to an wild-type 6-month old mouse lung and a 6-month old gcn2-deficient mouse lung. This will let us see if there is indeed an age-dependent factor; and to pinpoint the specific cell types in the lung that are changing with age. 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。2我们在试图找出GCN 2缺失如何以及为什么会导致肺动脉高压方面取得了进展--我们已经证明，缺乏这种基因的小鼠也会出现轻度肺动脉高压，当他们长大后（5-6个月），他们的肺部和血液中也有炎症标志物。然而，给予GCN 2缺陷细胞模型炎症刺激并没有引起更严重的反应。当小鼠在较年轻时接受炎症刺激时，也不会发生这种情况，因此我们假设年龄是GCN 2相关肺血管表型的一个促成因素。我们正在通过suimultimate比较所有来自未处理的8周野生型小鼠肺的细胞，未处理的8周gcn 2缺陷小鼠肺，野生型6个月大的小鼠肺和6个月大的gcn 2缺陷小鼠肺。这将让我们看看是否确实存在年龄依赖性因素;并确定肺部随年龄变化的特定细胞类型。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

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

Unpicking the Effects of General Control Non-depressible 2 (GCN2) Deficiency in Pulmonary Veno-Occlusive Disease

揭示一般控制非抑制性 2 (GCN2) 缺陷对肺静脉闭塞性疾病的影响

• DOI: 10.1183/13993003.congress-2023.oa3155
• 发表时间: 2023
• 作者: Schwiening M