Genetic Analysis of Murine Chronic Hypoxia-Induced Pulmonary Hypertension

小鼠慢性缺氧性肺动脉高压的遗传分析

• 批准号: 8448138
• 负责人: WILLIAM C NICHOLS
• 金额: $ 66.32万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448138
• 关键词: Animals; Backcrossings; Candidate Disease Gene; Cause of Death; Characteristics; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Computer software; Control Locus; Data; Databases; Development; Disease; Employment; Exposure to; Functional disorder; Gene Expression; Genes; Genetic; Genotype; Goals; Haplotypes; Health; Heart; Heart failure; Hematocrit procedure; Heritability; Human; Hypoxia; Inbred Strain; Individual; Interstitial Lung Diseases; Knowledge; Lung; Maps; Measures; Methods; Microarray Analysis; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Obstructive Lung Diseases; Parents; Pathogenesis; Patients; Phenotype; Play; Population; Predisposition; Pulmonary Hypertension; Pulmonary artery structure; Quantitative Trait Loci; Right Ventricular Dysfunction; Right Ventricular Hypertrophy; Role; Single Nucleotide Polymorphism; Surveys; Systolic Pressure; Techniques; Testing; Therapeutic Agents; Ventricular; base; genetic analysis; heart function; interstitial; mortality; mouse genome; mouse model; novel therapeutics; phenome; pressure; prevent; public health relevance; pulmonary arterial hypertension; response; trait

DESCRIPTION (provided by applicant): This application is in response to PA-07-043 Right Heart Function in Health and Chronic Lung Diseases. There are approximately 100,000 new pulmonary hypertension (PH) patients annually in the U.S., and 50,000- 300,000 new cases of interstitial and chronic obstructive lung diseases (COPD) respectively. It is widely recognized that right ventricular dysfunction plays a pivotal role in heart failure in patients with pulmonary arterial hypertension (PAH), interstitial lung diseases and COPD. Right heart failure is the leading cause of mortality in PAH and contributes significantly to mortality in interstitial and obstructive lung diseases. A better understanding of right heart dysfunction in these diseases will likely enable new therapies to prevent or treat right heart failure, resulting in reduced morbidity and mortality in these patients. In spite of this, our understanding of the pathogenesis of right ventricular dysfunction in these diseases is very limited and even less is known about genes that influence the susceptibility for right ventricular hypertrophy (RVH) and elevated pulmonary artery pressure (PAP). We hypothesize that genetic differences between individuals and/or within populations play a major role in determining the susceptibility to RVH and/or elevated right ventricular systolic pressure (RVSP) in chronic lung disease such as PAH. Employing a well-established mouse model of PH induced by exposure to chronic hypoxia, we will identify strain specific differences in right ventricular dysfunction. Our preliminary data already clearly indicates that major differences exist between different strains. The primary objective of this application is to identify specific regions of the mouse genome containing genes contributing to increased susceptibility to chronic hypoxia-induced PH. To achieve this, the following specific aims are proposed: 1) Survey inbred strains to determine appropriate mouse models for genetic analysis of chronic hypoxia-induced pulmonary hypertension; 2) Perform conventional mapping to identify quantitative trait loci (QTLs) contributing to chronic hypoxia-induced PH. Strains demonstrating the largest differences in RVH and RVSP after chronic hypoxia will be selected as models for QTL analysis; 3) Identify candidate and positional candidate genes associated with susceptibility to chronic hypoxia-induced pulmonary hypertension for each mouse model within identified QTL regions. Fine mapping with additional single nucleotide polymorphisms in the QTL regions, recently developed haplotype association mapping methods of the QTL regions, and microarray analysis of parental and F2 animals for each model will be performed to refine the regions and identify any genes in the QTL regions demonstrating changes in gene expression. These genes can be prioritized as potential quantitative trait candidate genes (QTGs).

描述（由申请人提供）：本申请是对PA-07-043健康和慢性肺部疾病的右心功能的响应。在美国，每年大约有10万例新发肺动脉高压（PH）患者，以及5万至30万例间质性和慢性阻塞性肺疾病（COPD）新发病例。右室功能障碍在肺动脉高压（PAH）、间质性肺疾病和COPD患者心力衰竭中起着关键作用，这一点已被广泛认识。右心衰是PAH患者死亡的主要原因，对间质性和阻塞性肺疾病的死亡率有显著影响。更好地了解这些疾病的右心功能障碍可能会带来新的治疗方法来预防或治疗右心衰，从而降低这些患者的发病率和死亡率。尽管如此，我们对这些疾病中右心室功能障碍的发病机制的了解非常有限，对影响右心室肥厚（RVH）和肺动脉压升高（PAP）易感性的基因的了解更少。我们假设个体之间和/或群体内的遗传差异在确定慢性肺部疾病（如PAH）中RVH和/或右心室收缩压升高（RVSP）的易感性方面起主要作用。通过建立小鼠慢性缺氧诱导的PH模型，我们将确定右心室功能障碍的菌株特异性差异。我们的初步数据已经清楚地表明，不同菌株之间存在重大差异。本应用程序的主要目的是确定小鼠基因组中含有增加慢性缺氧诱导ph易感性的基因的特定区域。为了实现这一目标，提出了以下具体目标：1)调查近交系，以确定适合慢性缺氧诱导肺动脉高压遗传分析的小鼠模型；2)常规作图，确定影响慢性缺氧ph的定量性状位点（QTL），选择慢性缺氧后RVH和RVSP差异最大的菌株作为QTL分析模型；3)在确定的QTL区域内，对每种小鼠模型确定与慢性缺氧性肺动脉高压易感性相关的候选基因和定位候选基因。对QTL区域中额外的单核苷酸多态性进行精细定位，最近开发的QTL区域单倍型关联定位方法，以及对每个模型的亲本和F2动物进行微阵列分析，以完善区域并识别QTL区域中显示基因表达变化的任何基因。这些基因可以作为潜在的数量性状候选基因（QTGs）被优先考虑。