Role of BMPR2 expression in HPAH; implications for novel therapeutic approaches

描述(申请人提供)：这个项目的长期目标是更好地了解遗传因素在肺动脉高压(PAH)发病机制中的作用，PAH是一种常染色体显性遗传性致命疾病。骨形态发生蛋白受体2(BMPR2)基因是转化生长因子(TGF-2)超家族成员之一，在大多数遗传型PAH(HPAH)中发现突变。HPAH的一个显著特征是其不完全外显--大多数致病突变携带者(~80%)没有临床症状，但可以产生受HPAH影响的后代。因此，突变携带者无法预测他或她是否会发展为临床疾病，这给突变携带者带来了焦虑，也给医生的治疗和后续治疗带来了不确定性。我们的提案旨在解决HPAH中的这一关键问题。我们的数据提示了HPAH发病机制的一个范式转换概念--野生型(WT)非突变BMPR2等位基因的表达水平可能是HPAH疾病外显性的主要决定因素。这突出了BMPR2表达在PAH发病机制中的重要性，并强调了更好地了解控制BMPR2表达的机制的必要性。基于这些数据，我们假设疾病与WT BMPR2等位基因在HPAH中的表达水平和BMPR2在特发性(I)PAH中的总表达水平有关。这项拟议的研究是遗传学家、基础科学家、统计学家和肺病学家之间的合作，将产生单一研究人员难以比拟的协同效应。这项拟议研究的基本原理是，了解BMPR2基因调控背后的遗传机制可以为HPAH提供更好的诊断和治疗选择。我们的具体目标如下。1.确定BMPR2表达在HPAH的疾病外显性中的作用及其在IPAH中的危险因素。2.确定在HPAH和IPAH患者中观察到的BMPR2表达变异的基因组和分子基础。3.确定潜在的多环芳烃新疗法。这项提议的设计是为了翻译性质。它提出了一种创新的范式，整合了临床和遗传数据以及最新的方法，如定量性状基因座定位和使用连接图数据库来回答HPAH中的关键未知因素，并使用这些信息来确定潜在的治疗靶点。我们的期望是：1)更好地了解控制BMPR2表达的遗传因素；2)开发具有临床诊断实用价值的疾病预测模型；3)确定PAH的新治疗方案。

DESCRIPTION (provided by applicant): The long-term objective of this project is to better understand the role of genetic factors in the pathogenesis of pulmonary arterial hypertension (PAH), which is an autosomal dominant fatal disease. Mutations in the bone morphogenic protein receptor 2 (BMPR2) gene, a member of the transforming growth factor (TGF-2) superfamily, are found in the majority of cases of the heritable type of PAH (HPAH). A striking feature of HPAH is its incomplete penetrance-a majority of pathogenic mutation carriers (~80%) show no clinical symptoms but can produce offspring that are affected by HPAH. Thus a mutation carrier cannot predict whether he or she will develop clinical disease, creating anxiety on the mutation carrier's part and uncertainty as to treatment and follow up on the physician's part. Our proposal is designed to address this key issue in HPAH. Our data suggest a paradigm-shifting concept for HPAH pathogenesis-that expression levels of the wild-type (WT) non-mutated BMPR2 allele may be the primary determinant of disease penetrance in HPAH. This highlights the importance of BMPR2 expression in PAH pathogenesis and emphasizes the need for better understanding of mechanisms that control BMPR2 expression. Based on these data we hypothesize that disease is linked to the expression level of the WT BMPR2 allele in HPAH and total BMPR2 expression in idiopathic (I) PAH. The proposed research is a collaboration between geneticists, basic scientists, statisticians and pulmonologists and will produce a synergistic effect that is not easily matched by a single investigator. The rationale for the proposed research is that understanding the genetic mechanisms behind BMPR2 gene regulation could lead to better diagnosis and treatment options for HPAH. Our specific aims are as follows. 1. Determine the role of BMPR2 expression in disease penetrance in HPAH and as a risk factor in IPAH. 2. Determine the genomic and molecular basis of the observed variability in BMPR2 expression in HPAH and IPAH patients. 3. Identify potential new PAH treatments. This proposal is designed to be translational in nature. It presents an innovative paradigm that integrates clinical and genetic data and state of the art approaches such as quantitative trait locus mapping and the use of the Connectivity Map database to answer key unknowns in HPAH and uses that information to identify potential therapeutic targets. It is our expectation that we will: 1) develop a better understanding of the genetic factors that control BMPR2 expression; 2) develop a predictive model of disease that will have clinical diagnostic utility; and 3) identify new treatment options for PAH.