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

肺动脉高压是一个术语，描述了一组疾病，这些疾病有以下共同特征：进出肺的血管血压水平升高，如果不治疗，会导致心力衰竭，最终死亡。有两种主要类型的肺动脉高压。在第一种类型中，阻塞发生在供肺的动脉的水平上(‘肺动脉高压’)，而在第二种类型中，阻塞发生在或低于引流肺的静脉的水平(‘肺静脉高压’)。最近发现了一种新的遗传性疾病，可导致一种罕见的肺动脉高压，即肺静脉闭塞症(PVOD)，它结合了动脉和静脉的特征。这个问题包括一种名为一般控制不可降压2，或GCN2的蛋白质的基因突变。GCN2蛋白在一种被称为综合应激反应的反应中至关重要，这种反应通常在蛋白质饥饿时期被激活。之前还没有任何迹象表明这种蛋白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。我们在试图找出GCN2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患上轻微的肺动脉高压，而且当它们长大(5-6个月)时，它们的肺部和血液中也有炎症的标志。然而，给予GCN2缺陷细胞模型炎性刺激并没有引起更严重的反应。当小鼠在更年轻的时候被给予炎症刺激时，也不会。因此，我们假设年龄是GCN2相关肺血管表型的一个促成因素。我们正在通过皮下比较来自未经处理的8周野生型小鼠肺、未经处理的8周GCN2缺陷小鼠肺、6个月大的野生型小鼠肺和6个月大的GCN2缺陷小鼠肺的所有细胞来测试这一点。这将让我们了解是否确实存在年龄相关的因素；并精确定位肺中随年龄变化的特定细胞类型。一旦我们了解了GCN2缺乏是如何导致小鼠发生肺动脉高压的，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在实验中得到支持。最终，我们的目标是开发治疗GCN2相关性肺动脉高压的新方法，并在患者的临床试验中进行测试。

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.