Modifying Genes in Pulmonary Hypertension

描述(由申请人提供)： 本次K08职业发展指导奖的目标是评估基因对肺动脉和动脉高压(PAH)发展的影响，PAH是一种进展性疾病，以平均肺动脉压升高、右心衰竭和死亡为特征。这一目标是基于一项发人深省的观察，即尽管进行了深入的研究，但严重肺动脉高压的自然进展和分子机制尚未被很好地了解。最近，家族性原发性肺动脉高压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，BMPRII是转化生长因子(TGF)超家族的成员之一。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生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。在这项K08应用中，PI将利用由NHLBI赞助的基因组应用计划(PhysGen、Hopgene和TIGR)提供的独特资源，并在已建立的大鼠肺动脉高压模型中应用当代遗传/基因组方法，以确定参与PAH发展的新基因。具体目标1将表征两个近交系大鼠(棕色挪威和SS Dahl)的PAH反应，PI表明它们对低氧的敏感性不同。特定目的2将利用一个共同的大鼠小组来识别对啮齿动物肺动脉高压反应的染色体特异性调节。这些染色体组大鼠只含有一条来自“抗性”亲本菌株的染色体，并将其导入“敏感”品系背景中，以便快速分离含有影响多环芳烃发生发展的基因的染色体(S)。具体目标3接下来将利用迅速产生的同源大鼠，以进一步定位感兴趣的区域(S)。这种方法与广泛的基因表达谱相结合，将使PI能够识别修改肺动脉高压反应的数量性状基因座(QTL)特定的候选基因。在大鼠身上获得的这些数据有可能识别相关的候选基因，这些候选基因可以改变人类PAH的易感性和严重性，利用可以在主要的Hopgene PGA中实施的高度翻译的方法。我们推测，这些分子靶点的阐明将导致对人类PAH所涉及的分子机制的新见解，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.