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

基本信息

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

项目摘要

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.

肺动脉高压是一个术语，描述一组具有以下共同特征的疾病：进出肺部的血管血压水平升高，如果不及时治疗，会导致心力衰竭，最终导致死亡。肺动脉高压有两种主要类型。在第一种类型中，阻塞发生在为肺部供血的动脉水平（“肺动脉高压”），而在第二种类型中，阻塞发生在引流肺部的静脉水平或以下（“肺静脉高压”））。最近发现了一种新的遗传问题，它可能导致一种罕见的肺动脉高压，即肺静脉闭塞病（PVOD），它结合了动脉和静脉的特征。这个问题是由一种称为通用控制非阻抑蛋白 2（GCN2）的蛋白质基因突变引起的。 GCN2 蛋白在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。此前没有任何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。我们在试图找出 GCN2 缺失如何以及为何导致肺动脉高压方面取得了进展 - 我们已经证明，缺乏该基因的小鼠也会出现轻度肺动脉高压，并且它们也具有标记物当他们年龄较大时（5-6 个月），肺部和血液会出现炎症。然而，给予 GCN2 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，它们也不会发生这种情况。因此，我们假设年龄是 GCN2 相关肺血管表型的一个影响因素。我们正在通过同时比较未经治疗的 8 周野生型小鼠肺、未经治疗的 8 周 gcn2 缺陷型小鼠肺、野生型 6 个月大的小鼠肺和 6 个月大的 gcn2 小鼠肺的所有细胞来测试这一点。 -小鼠肺缺陷。这将让我们看看是否确实存在与年龄相关的因素；并查明肺部随年龄变化的特定细胞类型。一旦我们了解了 GCN2 缺乏如何导致小鼠出现肺动脉高压，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，我们的目标是开发治疗 GCN2 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。