Role of the X-chromosome in Pulmonary Arterial Hypertension

X 染色体在肺动脉高压中的作用

• 批准号: 8211964
• 负责人: Micheala A Aldred
• 金额: $ 7.85万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-23 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8211964
• 关键词: Affect; Alleles; Androgen Receptor; Blood; Cells; Characteristics; Chromosome Deletion; Chromosome abnormality; Clonal Expansion; Clonality; Complex; Connective Tissue Diseases; Development; Disease; Embryonic Development; Endothelial Cells; Epigenetic Process; Etiology; Female; Frequencies; Functional RNA; Future; Gene Expression; Gene Mutation; General Population; Generations; Genes; Genetic; Goals; Growth; HUMARA gene analysis; Heart; Heart failure; In Situ; In Situ Hybridization; Incidence; Individual; Lead; Lesion; Life; Link; Lung; Lung Transplantation; Lung diseases; Malignant Neoplasms; Measures; Methylation; Microsatellite Instability; Modeling; Molecular; Morphologic artifacts; Mutation; Neoplasms; Normal tissue morphology; Pathogenesis; Patients; Pattern; Population; Primary Cell Cultures; Process; Pulmonary artery structure; Receptor Gene; Reporting; Role; Sampling; Shunt Device; Smooth Muscle Myocytes; Structure of parenchyma of lung; Techniques; Technology; Testing; Tissues; X Chromosome; X Inactivation; abstracting; arteriole; base; design; effective therapy; exome; experience; in vivo; male; neoplastic; next generation; novel; pressure; promoter; pulmonary arterial hypertension; pulmonary artery endothelial cell

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a serious lung disease characterized by proliferative changes in the small pulmonary arteries that leads to vessel narrowing, elevated pulmonary artery pressure and right heart failure. There is growing evidence that proliferative lesions in the lungs of PAH patients are akin to neoplasia, with monoclonal expansion and genetic instability. Supporting this, we recently identified chromosomal abnormalities in endothelial cells from PAH lungs, including mosaic deletions of the X-chromosome in 16% of female cases. We have also found a surprisingly high frequency (32%) of very skewed X-inactivation patterns, which may represent monoclonality or reactivation of the inactive X-chromosome. In this study we will conduct a detailed analysis of X-inactivation in primary cell cultures and uncultured lung tissue to distinguish these two hypotheses and also identify whether cases with X-chromosome deletion have lost the active or inactive X. Allele-specific expression of X- linked genes will be analyzed using next generation sequencing and in situ hybridization will be performed to visualize X-chromosome copy number and XIST expression, a marker of X-inactivation, in uncultured tissue sections. Determining the frequency of monoclonality is critical to the neoplasia-like model for PAH pathogenesis and other abnormalities of the X-chromosome may in part explain the higher incidence in females than males. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension (PAH) is a serious, potentially life-threatening lung disorder with a complex etiology. This study will use lung tissue from patients with PAH who have undergone lung transplantation to characterize changes in the X-chromosome that occur during the course of the disease. The long-term goal is to understand how PAH develops and design more effective treatments. (End of Abstract)

描述（由申请人提供）：肺动脉高压（PAH）是一种严重的肺部疾病，其特征是小肺动脉的增生性改变，导致血管狭窄、肺动脉压升高和右心衰。越来越多的证据表明，PAH患者肺部的增生性病变与肿瘤类似，具有单克隆扩张和遗传不稳定性。为了支持这一点，我们最近在多环芳烃肺内皮细胞中发现了染色体异常，包括16%的女性病例中x染色体的马赛克缺失。我们还发现了一个惊人的高频率（32%）非常偏斜的x染色体失活模式，这可能代表单克隆性或失活的x染色体的再激活。在本研究中，我们将对原代细胞培养物和未培养肺组织中的X失活进行详细分析，以区分这两种假设，并确定X染色体缺失的病例是失去了活性X还是失活X。X连锁基因的等位基因特异性表达将使用下一代测序进行分析，并将进行原位杂交以可视化X染色体拷贝数和X失活标记物XIST的表达。在未培养组织切片中。确定单克隆的频率对于多环芳烃发病机制的肿瘤样模型至关重要，x染色体的其他异常可能部分解释了女性发病率高于男性的原因。