Mechanisms underlying the development of pulmonary arterial hypertension

严重的肺动脉高压(PAH)是一种罕见但毁灭性的疾病，极大地缩短了预期寿命。这种疾病被定义为局限于肺部的高血压。现有的治疗方法会在一段时间内改善症状，但大多数患者最终会恶化，需要升级治疗或肺移植。许多人最终会死于心力衰竭。如果我们对根本原因有更深入的了解，我们就能更好地找到治疗这种疾病的方法。我们已经从这种疾病的基因发现中学到了很多。大约25%的重度PAH患者携带一种名为BMPR2的基因缺陷(突变)。BMPR2基因编码一种蛋白质，通常存在于血管内壁细胞的表面。这种蛋白质向细胞内部发送信号，以防止细胞泄漏和死亡。当BMPR2突变时，血管内的细胞行为异常，导致肺动脉严重狭窄。目前可用的治疗方法并不影响这个潜在的问题，因此对疾病过程的影响很小。这个项目将解决这一领域的主要研究问题，目的是更好地了解疾病的机制，并为我们如何最好地治疗这种疾病提供新的线索。我们现在打算利用现代基因技术的力量，在我们排除了BMPR2突变的PAH患者中发现进一步的突变。自发现BMPR2突变以来的过去十年里，我们在治疗方面找到了有希望的线索，但这些并不直接。预测是，仔细寻找进一步的突变将为我们提供更多的靶点，这些靶点可能更容易转变为新的治疗方法。我们知道，在BMPR2突变患者的家庭中，有许多突变的个体尚未患上这种疾病。这一群体面临患PAH的主要风险，但引发该疾病的环境因素尚不清楚。我们计划在未来5年内对携带BMPR2突变但尚未患上这种疾病的受试者进行跟踪调查。在每月6次的随访中，受试者将提供血液样本，接受临床疾病体征评估，并将参加旨在检测环境暴露的问卷调查。研究的这一部分将提供有关某些突变个体的风险的重要信息，并提供有关疾病潜在触发因素的新信息，然后可以避免这些信息或利用这些信息设计新的治疗方法。作为这项研究的一部分，我们还将准备利用从遗传和环境信息中获得的信息。为了做到这一点，我们将从血液测试中产生患者特有的干细胞，这些干细胞来自BMPR2突变患者(有病和无病)和我们在其中发现新突变的患者。我们将开始使用这些细胞来了解突变如何导致这种疾病中重要细胞类型的变化，包括心脏和血管细胞，并将其作为筛选新药的一种手段。最后，我们将开始使用患者来源的样本(干细胞和血管细胞)来测试我们迄今最好的想法，这是基于我们从现有的遗传信息中了解到的。这项权威的全国性研究有可能为我们理解多环芳烃的遗传和环境原因提供重要的新见解，并有可能根据这些发现提供有希望的疾病预防或治疗的新方法。

Severe pulmonary arterial hypertension (PAH) is a rare but devastating condition with greatly reduced life expectancy. The disease is defined as high blood pressure confined to the lungs. Existing treatments improve symptoms for a time but the majority of patients eventually deteriorate and require escalation of therapy or lung transplantation. Many will eventually die from heart failure. We would be better placed to find curative treatments for this condition if we had a deeper understanding of the underlying causes. We have already learned much from genetic discoveries in this disease. Approximately 25% of patients with severe PAH carry defects (mutations) in a gene called BMPR2. The BMPR2 gene codes for a protein that is normally found on the surface of cells that line the inner walls of blood vessels. This protein sends signals to the inside of the cell to prevent it leaking and dying. When BMPR2 is mutated, the cells lining the blood vessels behave abnormally which leads to severe narrowing of the lung arteries. Currently available treatments do not affect this underlying problem and so have little if any effect on the disease process. This project will address major research questions in this field with the aim of providing a greater understanding of disease mechanisms and new clues as to how we can best treat this condition. We now intend to employ the power of modern genetic techniques to find further mutations in patients with PAH in whom we have excluded mutations in BMPR2. Over the last ten years since the discovery of mutations in BMPR2 we have found promising leads in terms of treatment, but these are not straightforward. The prediction is that looking closely for further mutations will provide us with additional targets that might be easier to transform into new treatments. We know that in the families of patients with BMPR2 mutations, there are many individuals with mutations who have not yet developed the disease. This group is at major risk of developing PAH but the environmental factors responsible for triggering the disease remain unknown. We plan to follow up subjects with BMPR2 mutations but who do not yet have the disease over the next 5 years. At 6 monthly follow up subjects will give blood samples, be assessed clinically for signs of disease and will compete a questionnaire designed to detect environmental exposures. This part of the study will provide important information on risk to individuals with certain mutations and provide new information on potential triggers for disease that can then be avoided or used to design new approaches to treatment. As part of this study we will also prepare to capitalise on information learned from the genetic and environmental information. To do this we will generate patient-specific stem cells from a blood test from individuals with BMPR2 mutations (with and without disease) and from patients in whom we find new mutations. We will begin to use these cells to understand how mutations cause changes in important cell types in this disease, including heart and blood vessel cells, and use this as a means of screening new drugs. Finally we will begin to use patient derived samples (stem cells and blood vessel cells) to test our best ideas so far, based on what we have learned from the available genetic information to date. This definitive national study has the potential to provide major new insights into our understanding of the genetic and environmental causes of PAH and has potential to provide promising new approaches to disease prevention or treatment based on these findings.