Pulmonary Fibrosis and Telomerase Dysfunction

描述(申请人提供)：肺纤维化的特征是以进行性的、不可逆转的肺结构破坏和气体交换中断为特征的一组不同类型的不可治愈的肺部疾病。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为三年。目前，这种疾病还没有有效的治疗方法。关于IPF分子机制的第一条线索来自两个小组(包括我们的小组)的发现，即肺纤维化的一个亚组是由编码端粒酶的蛋白质成分(TERT)和RNA成分(TERC)的基因突变引起的，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。在我们的研究中，所有端粒酶突变的受影响成员都有证据表明循环中白细胞的端粒长度缩短。然而，这些基因的突变在家族性疾病患者中不到15%，在更常见的散发性疾病患者中不到3%。在这里，我们将在一大批家族性和散发性肺纤维化受试者中描述肺纤维化的遗传病因。首先，我们将确定在没有端粒酶突变的受试者中，端粒功能障碍和端粒缩短是否是家族性和散发性肺纤维化的更普遍的特征，正如我们的初步研究所表明的那样。其次，我们将确定在没有端粒酶编码突变的患者亚群中，与端粒维持有关的其他基因的突变是否会导致PF。第三，我们将绘制在大家族中导致肺纤维化的新的基因位点，在这些大家族中，这种疾病未能与已知的导致肺疤痕形成的基因共分离。这些研究有可能为确定肺纤维化的潜在分子发病机制开辟新的概念基础。我们的多管齐下的方法为这种致命的、与年龄相关的肺部疾病的治疗干预提供了新的靶点。公共卫生相关性：特发性肺纤维化(IPF)是一组以进行性、不可逆转、肺瘢痕形成为特征的致命性疾病的原型。关于这种疾病的遗传基础的最新线索来自我们的发现，编码端粒酶的基因突变导致了常染色体显性遗传性肺纤维化家系的疾病。在这笔赠款中，我们将通过对患有这种破坏性疾病的患者及其家人进行综合的临床和遗传学方法来研究端粒酶功能障碍和肺纤维化之间的联系。

DESCRIPTION (provided by applicant): Pulmonary fibrosis characterizes a heterogeneous group of incurable lung disorders with progressive, irreversible destruction of the lung architecture and disruption of gas exchange. The prototype of these diseases, idiopathic pulmonary fibrosis (IPF), has a median life expectancy of three years from diagnosis to death. Currently, no effective treatment is available for this disease. The first clue as to the molecular mechanism responsible for IPF emerged from the discovery by two groups, including our group, that a subset of pulmonary fibrosis is caused by mutations in the genes encoding the protein component (TERT) and the RNA component (TERC) of telomerase, a ribonucleoprotein enzyme that catalyzes the addition of hexameric nucleotide repeats to the ends of linear chromosomes. In our studies, all affected members with mutations in telomerase have evidence of shortened telomere lengths in circulating leukocytes. However, mutations in these genes comprise less than 15% of patients with the familial form of the disease and less than 3% of patients with the more common sporadic form of the disease. Here we will characterize the genetic etiology of pulmonary fibrosis in a large collection of familial and sporadic pulmonary fibrosis subjects. First, we will determine if telomere dysfunction and telomere shortening is a more generalized feature of familial and sporadic pulmonary fibrosis in subjects who do not have telomerase mutations, as our preliminary studies suggest. Second, we will determine if mutations in other genes involved in telomere maintenance contribute to PF in the subset of patients without coding mutations in telomerase. Third, we will map new genetic loci that cause pulmonary fibrosis in large kindreds where the disease fails to co-segregate with the genes known to cause lung scarring. These studies have the potential for breaking new conceptual grounds for determining the underlying molecular pathogenesis of pulmonary fibrosis. Our multi-pronged approaches offer the promise of providing new targets for therapeutic intervention for this lethal, age-associated lung disease. PUBLIC HEALTH RELEVANCE: Idiopathic pulmonary fibrosis (IPF) is the prototype of a group of lethal diseases characterized by progressive, irreversible, lung scarring. A recent clue as to the genetic underpinnings of this disorder came from our finding that mutations in the genes encoding telomerase cause the disease in a subset of families with autosomal dominant pulmonary fibrosis. In this grant we will investigate the link between telomerase dysfunction and pulmonary fibrosis through an integrated, clinical and genetic approach to patients and their families with this devastating disorder.