Modifying Genes in Pulmonary Hypertension

修改肺动脉高压基因

• 批准号: 7446722
• 负责人: ARI L ZAIMAN
• 金额: $ 13.31万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7446722
• 关键词: Address; Affect; Backcrossings; Candidate Disease Gene; Cessation of life; Chromosomes; Data; Defect; Development; Disease; Elevation; Environment; Evaluation; Family; Gene Expression Profiling; Gene Mutation; Gene-Modified; Genes; Genetic; Genomics; Goals; Heart failure; Human; Hypertension; Hypoxia; Immunohistochemistry; Inbred Strains Rats; Individual; Investigation; K-Series Research Career Programs; Lead; Localized; Lung; Maps; Measurement; Mentors; Modeling; Molecular; Molecular Profiling; Molecular Target; Mutation; Northern Blotting; Norway; Parents; Pathogenesis; Patients; Persons; Physiological; Polymerase Chain Reaction; Predisposition; Progressive Disease; Pulmonary Hypertension; Pulmonary artery structure; Quantitative Trait Loci; Rat Strains; Rat-1; Rattus; Regulation; Resistance; Resources; Risk; Rodent; Role; Scheme; Scientist; Severities; Single Nucleotide Polymorphism; Testing; Transforming Growth Factors; Variant; Vascular Endothelial Growth Factors; base; bone morphogenetic protein receptor type II; congenic; consomic; improved; inhibitor/antagonist; insight; interest; lung hypoxia; member; novel; novel strategies; outcome forecast; pressure; primary pulmonary hypertension; programs; pulmonary arterial hypertension; response; sobriety; therapy design; translational approach

DESCRIPTION (provided by applicant): The goal of this K08 Mentored Career Development Award is to evaluate genetic influences in the development of pulmonary and arterial hypertension (PAH), a progressive disease characterized by an elevation in the mean pulmonary artery pressure, right heart failure, and death. This goal is based on the sobering observation that despite intensive investigation, the natural progression and the molecular mechanisms underlying the development of severe pulmonary hypertension are not well understood. Recently, genetic studies of familial primary pulmonary hypertension (FPPH) elucidated alterations in the bone morphogenetic protein receptor II (BMPRII) gene, a member of the transforming growth factor (TGF) super-family. However, although about 50% of patients with FPPH have this gene defect, only 20% of persons carrying a mutation in this gene develop PAH, clearly implicating additional host/environment interactions involving modifier genes that influence the development of PAH. In this K08 application, the PI will leverage the unique resources provided by the NHLBI-sponsored Programs in Genomic Applications (PhysGen, HopGene and TIGR) and apply contemporary genetic/genomic approaches in an established rat model of pulmonary hypertension in order to identify novel genes which are involved in the development of PAH. Specific Aim 1 will characterize PAH responses in two inbred rat strains (Brown Norway and SS Dahl) shown by the PI to differ in their susceptibility to hypoxia. Specific Aim 2 will utilize a consomic rat panel to identify chromosome-specific regulation of the rodent pulmonary hypertensive response. These consomic rats contain a single chromosome from the "resistant" parent strain introgressed into the "sensitive" strain background in order to allow the rapid isolation of the chromosome(s) containing genes that influence the development of PAH. Specific Aim 3 will next utilize congenic rats which have been rapidly generated in order to further localize the region(s) of interest. This approach, combined with extensive gene expression profiling, will allow the PI to identify quantitative trait loci (QTL)-specific candidate genes that modify the pulmonary hypertensive response. These data obtained in rats have the potential to identify relevant candidate genes which modify the susceptibility and severity of PAH in humans, utilizing highly translational approaches that can be implemented within the overarching HopGene PGA. We speculate that the elucidation of these molecular targets will lead to novel insights into the molecular mechanisms involved in human PAH and provide the rationale for novel therapies designed to improve the prognosis of patients with this devastating disease.

描述（由申请人提供）： K08 指导职业发展奖的目标是评估肺动脉高压 (PAH) 发展中的遗传影响，这是一种以平均肺动脉压升高、右心衰竭和死亡为特征的进行性疾病。 这一目标是基于一个发人深省的观察，即尽管进行了深入的研究，但严重肺动脉高压发展的自然进展和分子机制尚不清楚。 最近，家族性原发性肺动脉高压 (FPPH) 的遗传学研究阐明了骨形态发生蛋白受体 II (BMPRII) 基因的改变，骨形态发生蛋白受体 II (BMPRII) 基因是转化生长因子 (TGF) 超家族的成员。 然而，尽管约 50% 的 FPPH 患者存在这种基因缺陷，但携带该基因突变的人中只有 20% 会患上 PAH，这清楚地表明涉及影响 PAH 发生的修饰基因的宿主/环境相互作用。 在本次 K08 申请中，PI 将利用 NHLBI 赞助的基因组应用项目（PhysGen、HopGene 和 TIGR）提供的独特资源，并在已建立的肺动脉高压大鼠模型中应用当代遗传/基因组方法，以确定与 PAH 发展有关的新基因。 具体目标 1 将表征两种近交大鼠品系（Brown挪威和 SS Dahl）的 PAH 反应特征，PI 表明它们对缺氧的敏感性不同。 具体目标 2 将利用小鼠群体来确定啮齿动物肺动脉高压反应的染色体特异性调节。 这些体鼠含有来自“抗性”亲本品系的单条染色体，渗入到“敏感”品系背景中，以便能够快速分离含有影响 PAH 发展的基因的染色体。 具体目标 3 接下来将利用快速生成的同类大鼠，以进一步定位感兴趣的区域。 这种方法与广泛的基因表达谱相结合，将使 PI 能够识别改变肺动脉高压反应的数量性状基因座 (QTL) 特异性候选基因。 利用可在总体 HopGene PGA 中实施的高度转化方法，在大鼠中获得的这些数据有可能识别出改变人类 PAH 易感性和严重程度的相关候选基因。 我们推测，这些分子靶标的阐明将为人类多环芳烃分子机制带来新的见解，并为旨在改善这种破坏性疾病患者预后的新疗法提供理论基础。