Genetic Analysis of Murine Chronic Hypoxia-Induced Pulmonary Hypertension

描述(申请人提供)：本申请是对PA-07-043《健康与慢性肺病的右心功能》的回应。美国每年约有10万新的肺动脉高压(PH)患者，间质性肺疾病和慢性阻塞性肺疾病(COPD)的新病例分别为50,000-300,000例。右心功能不全在肺动脉高压(PAH)、间质性肺疾病和慢性阻塞性肺疾病(COPD)患者心力衰竭中起重要作用。右心衰竭是PAH死亡的主要原因，也是间质性和阻塞性肺疾病死亡的主要原因。更好地了解这些疾病中的右心功能障碍可能会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，我们对这些疾病右室功能不全的发病机制的了解非常有限，对影响右室肥厚(RVH)和肺动脉压(PAP)升高的易感性的基因更是知之甚少。我们假设个体之间和/或群体内的遗传差异在决定慢性肺部疾病(如PAH)中RVH和/或右室收缩压(RVSP)升高的易感性中起主要作用。利用一个已建立的慢性低氧诱导的小鼠肺动脉高压模型，我们将确定右室功能障碍的品系特异性差异。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。这项应用的主要目标是确定小鼠基因组中包含导致对慢性低氧诱导的PH易感性增加的基因的特定区域。为了实现这一目标，提出了以下具体目标：1)调查近交系，以确定合适的小鼠模型用于慢性缺氧性肺动脉高压的遗传分析；2)进行常规定位，以确定与慢性缺氧性肺动脉高压有关的数量性状基因座(QTL)。选择慢性低氧后RVH和RVSP差异最大的品系作为QTL分析的模型；3)在已确定的QTL区域内为每个小鼠模型寻找与慢性低氧性肺动脉高压易感性相关的候选和位置候选基因。将进行精细定位和QTL区域额外的单核苷酸多态，最近开发的QTL区域单倍型关联定位方法，以及针对每个模型的亲本和F2动物的微阵列分析，以改进区域并识别QTL区域中任何显示基因表达变化的基因。这些基因可能是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10万新的肺动脉高压患者，间质性肺疾病和慢性阻塞性肺疾病的新病例分别为50,000-300,000例。众所周知，右室功能障碍在肺动脉高压(PAH)、间质性肺疾病和慢性阻塞性肺疾病(COPD)患者心力衰竭中起重要作用。右心衰竭是PAH死亡的主要原因，也是间质性和阻塞性肺疾病死亡的主要原因。利用一个公认的慢性低氧引起的小鼠肺动脉高压模型，我们将识别右室功能障碍的品系特异性差异。这项应用的主要目标是确定小鼠基因组的特定区域，该区域包含导致慢性低氧引起的右室肥厚和/或右室收缩压升高的易感性增加的基因。更好地了解这些疾病中右心功能不全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。

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.