Pulmonary Fibrosis and Telomerase Dysfunction

 描述(申请人提供)：肺纤维化的特征是一组不同类型的肺部疾病，肺部结构受到不可逆转的破坏，气体交换中断。这些疾病的原型是特发性肺纤维化(IPF)，从确诊到死亡的平均预期寿命很短。端粒酶的蛋白质组分(TERT)或RNA组分(TERC)编码基因的突变会导致家族性肺纤维化家族性疾病。端粒酶是一种核糖核蛋白酶，催化将六聚体核苷酸重复添加到线性染色体的末端。同样数量的家系有端粒酶功能障碍的证据，外周血端粒长度非常短，但端粒酶基因没有编码突变。我们的假设是，端粒长度较短，由TERT或TERC以外的基因突变引起，是IPF的重要机制。在这项赠款申请中，我们将传统的临床表型和连锁方法与新一代外显子组测序相结合，以提供对IPF遗传学的新见解。首先，我们将描述与非常短的端粒长度相关的罕见家系的临床表型，这些家系显示出常染色体显性共同分离的肺纤维化和短的端粒长度。由于极端表型是基因发现的有力工具，我们将使用临床评估和分析组织端粒酶表达、肺转录组特征和循环生物标记物来表征短端粒IPF表型。其次，我们将使用下一代外显子组测序来识别在已知的家族性肺纤维化基因中没有突变的家系队列中罕见的候选变异。这些数据集将通过四种独立的方法进行筛选和优先排序：(1)根据与肺纤维化和/或短端粒长度的表型共同分离的基因组区域，(2)根据等位基因频率，(3)根据对蛋白质功能的预测有害影响，以及(4)基于b基因的频率及其在端粒和纤维化通路中的生物学作用。最终目标将通过在被发现的家族中共分离、通过关联研究和通过对蛋白质变异功能的调查来验证候选变异。这些研究有可能通过确定端粒缩短如何导致肺纤维化来开辟新的领域。我们的多管齐下的方法为治疗干预提供了新的靶点，并将导致更好地理解端粒酶功能障碍引起的进行性肺纤维化的发病机制。

 DESCRIPTION (provided by applicant): Pulmonary fibrosis characterizes a heterogeneous group of lung disorders with irreversible destruction of lung architecture and disruption of gas exchange. The prototype of these diseases, idiopathic pulmonary fibrosis (IPF), has a short median life expectancy from diagnosis to death. Mutations in the genes encoding the protein component (TERT) or RNA component (TERC) of telomerase, a ribonucleoprotein enzyme that catalyzes the addition of hexameric nucleotide repeats to the ends of linear chromosomes, cause disease in a subset of kindreds with familial pulmonary fibrosis. An equal number of families has evidence of telomerase dysfunction, with very short peripheral blood telomere lengths, but no coding mutations in the telomerase genes. Our hypothesis is that short telomere lengths, caused by mutations in genes other than TERT or TERC, represent an important mechanism underlying IPF. In this grant application we merge traditional clinical phenotyping and linkage methods with next generation exome sequencing to provide new insights into IPF genetics. First, we will characterize the clinical phenotype associated with very short telomere lengths in rare kindreds that demonstrate autosomal dominant co-segregation of pulmonary fibrosis and short telomere lengths. Since extreme phenotypes represent a powerful tool for gene discovery, we will use clinical evaluations and analyses of tissue telomerase expression, lung transcriptome signatures and circulating biomarkers to characterize the short telomere IPF phenotype. Second, we will use next generation exome sequencing to identify rare candidate variants in the discovery cohort of kindreds without mutations in known familial pulmonary fibrosis genes. The datasets will be filtered and prioritized by four independent methods: (1) by genomic regions co- segregating with the phenotypes of lung fibrosis and/or short telomere length, (2) by allele frequency, (3) by predicted deleterious effects on protein function and (4) b gene-based frequencies and their biological roles in telomere and fibrosis pathways. The final aim will validate candidate variants by co-segregation in the kindreds they were discovered, by association studies and by investigations of protein variant function. These studies have the potential to break new grounds by determining how telomere shortening leads to lung fibrosis. Our multi-pronged approach offers the promise of new targets for therapeutic intervention and will lead to better understanding of the pathogenesis of progressive lung fibrosis due to telomerase dysfunction.