Genetic and Environmental Pathogenesis of PPH

描述(由申请人提供)： 原发性肺动脉高压(PPH)是一种进行性的、致命的疾病，它威胁着各个年龄段数千名患者的生命。在最近的一个重要进展中，骨形态发生蛋白受体2(BMPR2)的突变与家族性和散发性PPH有关。我们的假设是，其他基因和生物事件参与了家族性PPH的发生，因为携带BMPR2突变的人中只有20%曾发生PPH。我们的目标是识别调节BMPR2突变的临床表达的修饰基因和环境特征；加深对BMPR2突变如何导致疾病的理解；以及识别导致PPH的未发现突变。该计划形成了一个结构基础，以加强来自六个学科的经验丰富的研究人员之间的现有合作，以优化PPH研究的进展。该计划将利用我们的数据库和样本库的独特资源，这些资源来自全美116个PPH家庭。在突变尚未确定的家系中，我们将寻找BMPR2基因的改变，包括启动子和内含子区域，并寻找可能证实2q33附近另一个基因座的机会重组事件。识别修饰基因的实验方法将包括全基因组单核苷酸多态性和在已知突变的大家族中进行微卫星扫描，检查线粒体DNA单倍型和作为修饰基因的候选基因，包括NOS-1、NOS-3和5-羟色胺转运体。我们将研究PPH高危家庭中的许多个体接受基因检测和咨询的风险和益处。我们还将在肺动脉高压的小鼠模型中确定BMPR2的遗传修饰物。我们将通过确定突变蛋白对信号通路的生化影响来确定BMPR2等位基因变异改变BMP信号转导的功能机制。该提案强调，将共同的主题、互补的专业知识和独特的技术整合到一个协调的计划中将更具创造性、更有成效，更有可能促进对PPH分子发病机制的理解。

DESCRIPTION (provided by applicant): Primary pulmonary hypertension (PPH) is a progressive, fatal disease, which threatens the lives of thousands of patients across all age groups. In a recent important advance, mutations in bone morphogenetic protein receptor 2 (BMPR2) have been associated with both familial and sporadic PPH. Our hypothesis is that other genes and biologic events participate in the development of familial PPH, because only 20% of persons with a BMPR2 mutation ever develop PPH. Our target goals are to identify the modifying genes and environmental features that regulate the clinical expression of mutations in BMPR2; to develop understanding about how BMPR2 mutations result in disease; and to identify the undiscovered mutations which cause PPH. The program forms a structural basis to enhance existing collaborations among experienced investigators from six disciplines to optimize progress in the study of PPH. The program will utilize the unique resources of our database and specimen bank developed from 116 PPH families across the US. In families with mutations not yet identified, we will search for alterations in the BMPR2 gene, including promoter and intronic regions, and search for chance recombination events which could confirm another locus near 2q33. Experimental approaches for identifying modifier genes will include genome wide single nucleotide polymorphism and microsatellite scans in large families with known mutations, examination of mitochondrial DNA haplotypes and candidate genes as modifiers, including NOS-1, NOS-3, and the serotonin transporter. We will study the perceived risks and benefits of genetic testing and counseling in many individuals in families at high risk for PPH. We will also identify genetic modifiers of BMPR2 in mouse models of pulmonary hypertension. We will determine the functional mechanisms by which variations found in the BMPR2 alleles alter BMP signal transduction by defining the biochemical effects of the mutant proteins on signaling pathways. The proposal emphasizes that the common themes, complementary expertise and unique technologies assembled into a coordinated program will be more creative, more productive and more likely to advance understanding of the molecular pathogenesis of PPH.