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

BMPR2 表达在 HPAH 中的作用；

• 批准号: 8107380
• 负责人: RIZWAN HAMID
• 金额: $ 45.41万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8107380
• 关键词: Address; Affect; Alleles; Anxiety; Bioinformatics; Clinic; Clinical; Collaborations; Collection; Data; Databases; Development; Diagnosis; Diagnostic; Disease; Employee Strikes; Etiology; FDA approved; Gene Expression Regulation; Genes; Genetic; Genomics; Goals; Haplotypes; Human; Individual; Inherited; Lead; Link; Lung; Maps; Measurable; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Mutate; Mutation; Nature; Pathogenesis; Pathway interactions; Patients; Penetrance; Pharmaceutical Preparations; Physicians; Physiological; Play; Predisposition; Pulmonary Hypertension; Quantitative Trait Loci; Regulation; Research; Research Personnel; Resources; Risk; Risk Factors; Role; Scientist; Symptoms; Time; Transforming Growth Factors; Uncertainty; United States; Vascular Endothelial Cell; base; bone morphogenic protein; design; disease diagnosis; disorder risk; drug candidate; expectation; follow-up; genetic risk factor; hypertension treatment; improved; innovation; insight; kindred; knockout gene; mRNA Expression; member; mortality; mouse model; mutation carrier; novel; novel therapeutic intervention; offspring; predictive modeling; pulmonary arterial hypertension; receptor; small hairpin RNA; therapeutic target; tool

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. PUBLIC HEALTH RELEVANCE: Project Diseases that result in PAH are a substantial cause of morbidity and mortality. The goal of this proposal is to provide insights into the role of BMPR2 expression in HPAH and IPAH. The ultimate goal is to determine whether this increased understanding could be put to use not only as a diagnostic tool in the clinic but also to identify FDA-approved drugs that may be candidates for PAH treatment. Our proposal leverages new bioinformatics tools and databases with the unique collection of resources available to us at Vanderbilt.

描述（由申请人提供）：本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致死性疾病。骨形态发生蛋白受体2（BMPR 2）基因（转化生长因子（TGF-2）超家族成员）的突变见于大多数遗传型PAH（HPAH）病例。HPAH的一个显著特征是其不完全突变-大多数致病突变携带者（约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，这对突变携带者来说是焦虑的，对医生来说是治疗和随访的不确定性。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，即野生型（WT）非突变BMPR 2等位基因的表达水平可能是HPAH疾病复发率的主要决定因素。这凸显了BMPR 2表达在PAH发病机制中的重要性，并强调需要更好地了解控制BMPR 2表达的机制。基于这些数据，我们假设疾病与HPAH中WT BMPR 2等位基因的表达水平和特发性（I）PAH中的总BMPR 2表达相关。这项拟议中的研究是遗传学家、基础科学家、统计学家和肺病学家之间的合作，将产生一种协同效应，这是单个研究者难以比拟的。这项研究的基本原理是，了解BMPR 2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BMPR 2表达在HPAH疾病复发中的作用以及作为IPAH的危险因素。2.确定HPAH和IPAH患者中观察到的BMPR 2表达变异性的基因组和分子基础。3.确定潜在的新PAH治疗方法。这项建议的目的是翻译性质。它提出了一种创新的范式，整合了临床和遗传数据以及最先进的方法，如数量性状基因座作图和使用连接图数据库来回答HPAH中的关键未知因素，并使用这些信息来识别潜在的治疗靶点。我们的期望是：1）更好地了解控制BMPR 2表达的遗传因素; 2）开发具有临床诊断实用性的疾病预测模型; 3）确定PAH的新治疗方案。 公共卫生相关性：项目导致PAH的疾病是发病率和死亡率的重要原因。该提案的目标是提供对BMPR 2表达在HPAH和IPAH中的作用的见解。最终目标是确定这种增加的理解是否不仅可以用作临床诊断工具，还可以用于识别FDA批准的可能用于PAH治疗的候选药物。我们的建议利用了新的生物信息学工具和数据库，以及范德比尔特提供给我们的独特资源。