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

肺动脉高压啮齿动物模型的基因组研究：经济学方法

• 批准号: 7331858
• 负责人: Ankit A Desai
• 金额: $ 5.29万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7331858
• 关键词: Attenuated; BAY 54-9085; Blood Vessels; Bone Morphogenetic Protein Receptor Gene; Candidate Disease Gene; Chromosomes; Chronic; Complex; Coupled; Data; Development; Disease; Environmental Risk Factor; Fatal Outcome; Gene Expression; Gene Expression Profiling; Gene Mutation; Gene Targeting; Gene-Modified; Genes; Genetic; Genetic Polymorphism; Genomics; Goals; Grant; Human; Hypertension; Hypoxia; Individual; Intervention; Knowledge; Lung; Modeling; Mutation; National Research Service Awards; Norway; Numbers; Other Genetics; Parents; Pathway interactions; Personal Satisfaction; Persons; Pharmaceutical Preparations; Play; Predisposition; Pulmonary Hypertension; Rat Strains; Rattus; Resistance; Rodent; Rodent Model; Role; SU 5416; Testing; Translating; Translational Research; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Vascular remodeling; attenuation; base; bone morphogenetic protein receptors; consomic; experience; improved; inhibitor/antagonist; kinase inhibitor; novel; novel therapeutics; pulmonary arterial hypertension; response; salt sensitive

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.

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 2 型骨形态发生蛋白受体基因 (BMPR2) 的突变。然而，只有 20% 携带 BMPR2 突变的人会患上肺PH。这强烈表明其他遗传多态性和环境因素对于启动导致疾病表达的病理序列是必要的。 NRSA 的这笔拨款将利用近交啮齿动物品系来帮助破译该疾病发展的遗传基础。一种新颖的经济学方法与已建立的啮齿动物 PH 模型中广泛的基因表达谱相结合，将用于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 减弱的多激酶抑制剂模型）的重要初步研究，我们寻求在该啮齿动物模型中识别候选基因，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。具体目标#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种啮齿动物品系中确定一系列强大的索拉非尼反应基因，该组合已被广泛认为是PH诱导和模拟药物人类严重的PH值。具体目标#2将通过使用含有来自渗入“敏感”菌株背景的“抗性”亲本菌株的单条染色体的体鼠，缩小位于已识别的索拉非尼响应染色体上的新靶基因的列表。这将使我们能够快速分离含有影响 PH 发展的基因的染色体。对这些大鼠获得的数据进行比较将能够识别和关注新的候选基因，这些基因可以改变人类对严重肺PH的血管反应。最终，对这些修饰基因的了解将使我们能够将这些信息转化为新的治疗途径，以改善疾病的致命结果，并为 PI 提供转化研究方面的出色经验。