Modifying Genes in Pulmonary Hypertension

描述（由申请人提供）： 该K 08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，PAH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。 这一目标是基于清醒的观察，尽管深入研究，严重肺动脉高压的自然进展和分子机制的发展还没有得到很好的理解。 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，该基因是转化生长因子（TGF）超家族的成员。 然而，尽管大约50%的FPPH患者有这种基因缺陷，但只有20%的携带该基因突变的人会发展为PAH，这显然意味着涉及影响PAH发展的修饰基因的额外宿主/环境相互作用。 在本K 08申请中，PI将利用NHLBI申办的基因组应用计划（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，以鉴定参与PAH发生的新基因。 具体目标1将描述PI显示的两种近交系大鼠品系（Brown Norway和SS Dahl）对缺氧敏感性不同的PAH反应。 具体目标2将利用一个consomic大鼠小组，以确定啮齿动物肺动脉高压反应的染色体特异性调节。 这些同源大鼠含有来自渗入“敏感”品系背景的“抗性”亲本品系的单个染色体，以便快速分离含有影响PAH发生的基因的染色体。 Specific Aim 3接下来将使用快速生成的同类大鼠，以进一步定位感兴趣区域。 这种方法，结合广泛的基因表达谱，将允许PI确定数量性状位点（QTL）的特定候选基因，修改肺动脉高压反应。 在大鼠中获得的这些数据有可能利用可在总体HopGene PGA内实施的高度翻译方法来鉴定改变人类PAH易感性和严重程度的相关候选基因。 我们推测，这些分子靶点的阐明将导致对人类PAH相关分子机制的新见解，并为旨在改善这种毁灭性疾病患者预后的新疗法提供理论基础。

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.