Mechanisms of Familial Pulmonary Fibrosis

描述（由申请人提供）： 该项目源于我们对家族性肺部疾病（包括家族性间质性肺炎（FIP））的长期兴趣。我们打算使用这个独特的FIP家族队列来研究导致进行性肺纤维化的潜在机制。该信息与散发性特发性肺纤维化（IPF）和其他形式的特发性间质性肺炎（IIP）患者高度相关。在家庭中调查肺纤维化有重要的优势。首先，有可能在这一群体中研究疾病的遗传原因。与疾病相关的三个基因，表面活性蛋白C和端粒酶复合物的成分，已经使用这些FIP家族进行了鉴定，这种鉴定导致了对疾病发病机制的新见解。其次，这一人群为我们提供了前所未有的机会，可以在疾病的最早阶段确定可以研究的症状前患者。这使我们能够研究疾病的主要表现，而不是由于进行性肺重塑而发生的病理生物学变化。项目1将通过高分辨率CT扫描确定有肺部放射学异常的FIP家族风险的症状前个体。有风险的个体（有和没有放射学异常）将接受支气管镜检查，以确定肺泡上皮细胞的表型特征，如ER应激，疱疹病毒感染或端粒缩短，有助于FIP的疾病进展。项目2将利用候选基因方法来识别和表征表面活性剂和端粒酶途径中的罕见遗传变体，以及已知与影响FIP发展的继发性肺纤维化相关的基因。项目3将进行一项连锁研究，以发现与FIP和散发性MP患者疾病相关的新遗传位点。其他研究将鉴定IIP患者肺组织中存在的病毒，并研究影响疾病表现的基因-基因和基因-环境相互作用。本计划中的综合方法将导致FIP和散发性IPF（以及其他形式的IIP）发病机制的新概念，并为新的治疗或预防策略提供机会。

DESCRIPTION (provided by applicant): This program has arisen from our long-standing interest in familial lung diseases, including familial interstitial pneumonia (FIP). We intend to use this unique cohort of families with FIP to investigate the underlying mechanisms that lead to progressive lung fibrosis. This information will be highly relevant to individuals with sporadic idiopathic pulmonary fibrosis (IPF) and other forms of idiopathic interstitial pneumonia (IIP). There are important advantages to investigating lung fibrosis in families. First, it is possible to study genetic causes of disease in this group. Three genes linked to disease, surfactant protein C and components of the telomerase complex, have already been identified using these FIP families, and this identification has led to new insights into disease pathogenesis. Second, this population allows us the unprecedented opportunity to identify pre-symptomatic patients that can be studied at the earliest stages of disease. This gives us the ability to study the primary manifestations of disease as opposed to pathobiological changes that occur as a result of progressive lung remodeling. Project 1 will identify pre-symptomatic individuals at risk for FIP families by high resolution CT scanning that have radiographic abnormalities in the lungs. At risk individuals (with and without radiographic abnormalities) will undergo bronchoscopy to identify phenotypic characteristics of alveolar epithelial cells, such as ER stress, herpesvirus infection, or telomere shortening that contribute to disease progression in FIP. Project 2 will utilize a candidate gene approach to identify and characterize rare genetic vanants in the surfactant and telomerase pathways, as well as genes known to be associated with secondary forms of pulmonary fibrosis, that impact development of FIP. Project 3 will perform a linkage study to discover new genetic loci associated with disease in FIP and sporadic MP patients. Additional studies will identify viruses present in lung tissue of patients with IIP and investigate gene-gene and gene-environment interactions that influence disease manifestation. The integrated approach in this Program will lead to new concepts in pathogenesis of FIP and sporadic IPF (as well as other forms of IIP), and suggest opportunities for novel treatment or prevention strategies.