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: 7859785
• 负责人: WILLIAM C NICHOLS
• 金额: $ 66.24万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7859785
• 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). PUBLIC HEALTH RELEVANCE: There are approximately 100,000 new pulmonary hypertension patients annually in the U.S., and 50,000- 300,000 new cases of interstitial and chronic obstructive lung diseases respectively. It is widely recognized that right ventricular (RV) dysfunction plays a pivotal role in heart failure in patients with pulmonary arterial hypertension (PAH), interstitial lung diseases and chronic obstructive pulmonary disease (COPD). Right heart failure is the leading cause of mortality in PAH and significantly contributes to mortality in interstitial and obstructive lung diseases. Employing a well-established mouse model of pulmonary hypertension induced by exposure to chronic hypoxia, we will identify strain specific differences in right ventricular dysfunction. The primary objective of this application is identify specific regions of the mouse genome containing genes contributing to increased susceptibility to chronic hypoxia-induced right ventricular hypertrophy and/or increased right ventricular systolic pressure. A better understanding of the genetics of right heart dysfunction in these diseases will likely enable new therapies to prevent and/or to treat right heart failure, resulting in reduced morbidity and mortality.

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中的右心功能的回应。在美国每年大约有100，000名新的肺动脉高压（PH）患者，间质性肺疾病和慢性阻塞性肺疾病（COPD）新发病例分别为5万~ 30万例。右心室功能不全是肺动脉高压、间质性肺疾病和COPD患者心力衰竭的重要原因。右心衰竭是PAH死亡的主要原因，并显著导致间质性和阻塞性肺疾病的死亡。更好地了解这些疾病中的右心功能不全可能使新的治疗方法能够预防或治疗右心衰竭，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，甚至更少的是知道影响右心室肥大（RVH）和肺动脉压升高（PAP）的易感性的基因。我们假设个体间和/或群体内的遗传差异在确定慢性肺病（如PAH）对RVH和/或右心室收缩压（RVSP）升高的易感性方面起着重要作用。采用一个完善的小鼠模型的PH诱导暴露于慢性缺氧，我们将确定应变具体的差异，右心室功能障碍。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。本申请的主要目的是鉴定小鼠基因组中含有对慢性缺氧诱导的肺动脉高压易感性增加有贡献的基因的特定区域。为了实现这一点，提出了以下具体目标：1）调查近交系以确定用于慢性缺氧诱导的肺动脉高压遗传分析的合适小鼠模型; 2）进行常规定位，以确定影响慢性低氧诱导的PH的数量性状基因座（QTL）。选择在慢性低氧后表现出最大RVH和RVSP差异的菌株作为QTL分析的模型; 3）在鉴定的QTL区域内鉴定与每个小鼠模型对慢性缺氧诱导的肺动脉高压的易感性相关的候选基因和位置候选基因。将使用QTL区域中额外的单核苷酸多态性进行精细作图，最近开发的QTL区域单倍型关联作图方法，以及对每个模型的亲本和F2动物进行微阵列分析，以细化区域并鉴定QTL区域中证明基因表达变化的任何基因。这些基因可以优先作为潜在的数量性状候选基因（QTGs）。 公共卫生相关性：美国每年约有100，000例新发肺动脉高压患者，间质性肺疾病和慢性阻塞性肺疾病的新发病例分别为5 - 30万例。右心室功能障碍是肺动脉高压、间质性肺疾病和慢性阻塞性肺疾病患者心力衰竭的重要原因。右心衰竭是PAH死亡的主要原因，并显著导致间质性和阻塞性肺疾病的死亡。利用长期缺氧诱导的肺动脉高压的成熟小鼠模型，我们将确定右心室功能障碍的品系特异性差异。本申请的主要目的是鉴定小鼠基因组的特定区域，所述特定区域含有有助于增加对慢性缺氧诱导的右心室肥大和/或增加的右心室收缩压的易感性的基因。更好地了解这些疾病中右心功能障碍的遗传学将可能使新的治疗方法能够预防和/或治疗右心衰竭，从而降低发病率和死亡率。