Pulmonary Fibrosis and Telomerase Dysfunction

肺纤维化和端粒酶功能障碍

• 批准号: 8035331
• 负责人: Christine Kim Garcia
• 金额: $ 44.85万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-06 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035331
• 关键词: Affect; Age; Architecture; Biological Assay; Candidate Disease Gene; Cell division; Cessation of life; Chromosomes; Cicatrix; Clinical; Code; Collection; Defect; Detection; Diagnosis; Disease; Enzymes; Ethnic Origin; Exons; Family; Family member; Functional Imaging; Functional disorder; Gases; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genomics; Grant; Hamman-Rich syndrome; Health; Human; Individual; Interstitial Lung Diseases; Length; Leukocytes; Life Expectancy; Link; Lung; Lung Transplantation; Lung diseases; Maps; Measures; Methods; Molecular; Mutation; Nucleotides; Pathogenesis; Patients; Population; Prevalence; Prevention; Proteins; Pulmonary Fibrosis; RNA; Ribonucleoproteins; Risk; Telomerase; Telomerase RNA Component; Telomere Maintenance; Telomere Shortening; Testing; Therapeutic Intervention; Variant; Work; autosomal dominant trait; case control; disease diagnosis; effective therapy; genetic linkage analysis; genetic variant; improved; insight; kindred; member; proband; prototype; sex; telomerase reverse transcriptase; telomere; tool

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.

描述（由申请人提供）：肺纤维化是一组异质性的不可治愈的肺部疾病，具有进行性、不可逆的肺结构破坏和气体交换中断。这些疾病的原型，特发性肺纤维化（IPF），从诊断到死亡的中位预期寿命为3年。目前，对这种疾病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研究小组（包括我们的研究小组）的发现，即肺纤维化的一个子集是由编码端粒酶蛋白组分（TERT）和RNA组分（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序列添加到线性染色体末端。在我们的研究中，所有端粒酶突变的受影响成员都有循环白细胞端粒长度缩短的证据。然而，这些基因中的突变包括不到15%的家族性疾病患者和不到3%的更常见的散发性疾病患者。在这里，我们将在大量的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，我们将确定端粒功能障碍和端粒缩短是否是没有端粒酶突变的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。第二，我们将确定是否在其他基因参与端粒的维护突变有助于PF的患者在没有编码突变的端粒酶亚组。第三，我们将绘制新的遗传基因位点，这些基因位点会导致肺纤维化，在这种疾病无法与已知的导致肺瘢痕形成的基因共分离的大kinds中。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。我们多管齐下的方法有望为这种致命的、与年龄相关的肺部疾病的治疗干预提供新的靶点。公共卫生关系：特发性肺纤维化（IPF）是一组以进行性、不可逆的肺瘢痕形成为特征的致死性疾病的原型。关于这种疾病的遗传基础的最新线索来自我们的发现，即编码端粒酶的基因突变导致常染色体显性肺纤维化家族中的一个子集的疾病。在这项资助中，我们将通过对患有这种毁灭性疾病的患者及其家属进行综合的临床和遗传方法，调查端粒酶功能障碍与肺纤维化之间的联系。