Progression of interstitial lung abnormalities: the role of imaging and telomere length regulation

项目摘要 特发性肺纤维化(IPF)是最常见和最严重的肺纤维化(PF)形式，正在增加 患病率高，中位生存期为3-5年。最近的研究终于证明，反 纤维化治疗可降低肺功能下降率，IPF仍是一种坚持不懈的进展性状态 部分原因是在提出报告时，PF处于高级阶段。还有证据表明，抗肝纤维化 治疗会减缓病情不太严重的患者的进展；这表明早期发现可能会 改善结果。Putman博士的研究表明，PF的早期阶段是可以检测到的，放射学 进展相对频繁，与IPF患者的遗传因素(例如MUC5B)相关 并与肺功能减退的速度加快和死亡风险增加有关。 尽管已经做了很多工作来证明成像分析可以检测到有助于 预测IPF的不良结局，目前尚不清楚ILA的哪些放射学特征最能预测加速 进展和死亡率。此外，大量研究表明，平均端粒长度 (MTL)，以及控制MTL的多个基因的变异与IPF和生存率降低有关， 这些决定ILA进展和死亡率的因素尚不清楚。 在第一个目标中，普特曼博士将确定最重要的放射学因素，无论是定性的还是定量的 与PF的进展相关，并将这些发现与临床结果联系起来。在第二个目标中，她 将探讨MTL降低与早期PF进展的关系。最后，在第三个 目的，利用全基因组测序数据，她将探索基因突变之间的关系 端粒酶途径与早期肺纤维化进展 这项工作将在布里格姆和妇女医院的肺部和危重护理医学部进行。 哈佛医学院核心教学医院(BWH)。普特曼博士将在以下条件下执行这项工作 早期肺纤维化领域的专家Hunninghake博士和Silverman博士的指导 慢性阻塞性肺疾病遗传学专家。在她的导师和科学顾问委员会的指导下，普特曼博士 制定了一个全面的五年培训计划，以发展成为一名独立的 具有复杂基因分析及其与图像表征相结合的专业知识的研究人员。 普特曼博士致力于学术医学的职业生涯。她的目标是成为一名临床医生和科学家 在这个奖项中获得的技能，以更好地理解导致PF的生物过程 发生和发展。她计划利用从这个奖项中获得的知识来研究下游 MTL降低的后果；最终目标是改善PF患者的护理和预后。

Project Summary Idiopathic pulmonary fibrosis (IPF), the most common and severe form of pulmonary fibrosis (PF), is increasing in prevalence, and has a median survival of 3-5 years. Recent studies have finally demonstrated that anti- fibrotic therapy can reduce the rate of decline in lung function, IPF remains a relentlessly progressive condition in part due to the advanced stages of PF at the time of presentation. There is also evidence that anti-fibrotic therapy reduces progression in patients with less severe disease; which suggests that early detection may improve outcomes. Dr. Putman’s work has shown that the early stages of PF are detectable, that radiologic progression is relatively frequent, is correlated with genetic factors seen in IPF patients (e.g. MUC5B genotype), and is associated with an accelerated rate of lung function decline and an increased risk of death. Although much work has been done to demonstrate that imaging analyses can detect patterns that help to predict adverse outcomes in IPF, it is unclear what radiologic characteristics of ILA best predict accelerated progression and mortality. Additionally, numerous studies have demonstrated that mean telomere length (MTL), and variants in multiple genes controlling MTL are associated with IPF and reduced survival, the role of these factors in determining the progression and mortality associated with ILA is not known. In the first aim, Dr. Putman will identify the radiologic factors, both qualitative and quantitative, that are most associated with the progression of PF, and relate these findings to clinical outcomes. In the second aim she will explore the relationship between reduced MTL and the progression of early stage PF. Finally, in the third aim, using whole genome sequencing data, she will explore the relationship between genetic mutations in the telomerase pathway and progression of early stage pulmonary fibrosis. This work will be performed in the Division of Pulmonary and Critical Care Medicine, at Brigham and Women’s Hospital (BWH), a core teaching hospital of Harvard Medical School. Dr. Putman will perform this work under the mentorship of Dr. Hunninghake, an expert in the field of early pulmonary fibrosis and Dr. Silverman, an expert in COPD genetics. With the guidance of her mentors and scientific advisory committee, Dr. Putman has developed a comprehensive five year training program to develop the skills needed to become an independent investigator with expertise in complex genetic analyses and their integration with image characterization. Dr. Putman is dedicated to a career in academic medicine. Her goal is to become a clinician-scientist using the skills gained during this award to better our understanding of the biologic processes that lead to PF occurrence and progression. She plans to use the knowledge gained from this award to study the downstream consequences of decreased MTL; with the ultimate goal of improving care and outcomes in patients with PF.