Genomic Studies in a Rodent Model of Pulmonary Hypertension: A Consomics Approach

描述（由申请人提供）：原发性和继发性肺动脉高压（PH）的遗传基础尚不清楚。最近，在-50%的家族性原发性ph病例中发现了骨形态发生蛋白受体2型基因（BMPR2）的突变。然而，只有20%具有这种BMPR2突变的人会发展为ph。这强烈表明，其他遗传多态性和环境因素是启动导致疾病表达的病理序列所必需的。这项NRSA拨款将利用近亲繁殖的啮齿动物菌株来帮助破译疾病发展的遗传基础。一种新的经济学方法，结合广泛的基因表达谱，在一个已建立的啮齿动物PH模型中，将被用来检验修饰基因参与严重肺动脉高压发展的假设。通过涉及药物索拉非尼（一种PH衰减的多激酶抑制剂模型）的重要初步研究，我们寻求在这种啮齿动物模型中确定候选基因，这将有助于更好地了解人类对PH的易感性和发展的多样性。特异性目标#1将在暴露于慢性缺氧和SU5416（一种血管内皮生长因子受体抑制剂）的3种啮齿动物菌株中确定sorafenib反应基因的强大菜单，SU5416已被确定为PH诱导和模拟人类严重PH。特异性目标#2将通过使用含有来自“抗性”亲本菌株渗入“敏感”菌株背景的单个染色体的经济大鼠，缩小位于已鉴定的sorafenib反应性染色体上的新靶基因列表。这将使我们能够快速分离出含有影响PH发展的基因的染色体。在这些大鼠中获得的数据进行比较，将有能力识别和关注新的候选基因，这些基因可以改变人类对严重PH的血管反应。最终，这些修饰基因的知识将使我们能够将信息转化为新的治疗途径，以改善疾病的致命结果，并为PI提供转化研究的杰出经验。

DESCRIPTION (provided by applicant): The genetic basis for primary and secondary pulmonary arterial hypertension (PH) is not known. Recently, mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2) have been identified in -50% of cases of familial Primary PH. Only 20% of persons with this BMPR2 mutation, however, develop PH. This strongly suggests that other genetic polymorphisms and environmental factors are necessary to initiate the pathological sequence that leads to expression of the disease. This NRSA grant will utilize inbred rodent strains to help decipher the genetic basis of the development of the disease. A novel consomics approach coupled to extensive gene expression profiling in an established rodent PH model will be utilized to test the hypothesis that modifier genes are involved in the development of severe pulmonary hypertension. Enabled by important preliminary studies involving the drug Sorafenib, a multi-kinase inhibitor model of PH attenuation, we seek to identify candidate genes in this rodent model which will help to better understand the diversity in susceptibility to and development of PH in humans. Specific Aim #1 will identify a robust menu of Sorafenib-responsive genes in 3 rodent strains that will be exposed to chronic hypoxia and SU5416 (a vascular endothelial growth factor receptor inhibitor), a combination which has been well established as PH- inducing and mimics severe PH in humans. Specific Aim #2 will narrow this list of novel target genes residing on identified Sorafenib-responsive chromosomes by employing consomic rats containing a single chromosome from a "resistant" parent strain introgressed into a "sensitive" strain background. This will allow us to rapidly isolate the chromosome(s) containing genes that influence the development of PH. Comparisons made on the data obtained in these rats will have the power to identify and focus new candidate genes that modify the vascular response to severe PH in humans. Ultimately, knowledge of these modifier genes will empower us to translate the information into novel therapeutic pathways to improve the fatal outcome of the disease and provide the PI an outstanding experience in translational research.