Molecular Markers of Idiopathic Pulmonary Fibrosis Progression

项目摘要 特发性肺纤维化（IPF）是一种病因不明的破坏性疾病，中位生存期仅为 2-3年IPF个体的疾病进展率差异很大。病情进展迅速 仅20-30%的患者发生，但导致75%的IPF相关死亡。临床医生面临的主要问题是 他们无法确定在不可逆肺栓塞后才会经历快速进展的患者， 功能下降。牛顿博士先前已经证明，端粒中的致病性遗传变异- 维持基因易于快速进展;然而，这些静态遗传变异本身并不 解释IPF临床病程的极端异质性。临床过程的变异性受到 环境暴露，如香烟烟雾或炎症，这可能会改变染色质结构， 基因调控元件的可用性，从而重新编程基因表达谱， IPF病程表型。因此，牛顿博士假设，整合染色质可及性 与基因表达的结合将允许发现新的分子标记和生物学相关的驱动因子 区分IPF病程表型的途径。沿着这些路线，他的具体目标是： 使用临床、基因组学、表观遗传学和基因识别具有短期快速进展高风险的IPF患者 表达特征，2）发现与以下相关的基因调控元件和生物学途径： IPF快速进展，和3）确定相应的染色质可及性和基因表达的变化 IPF急性加重。为了实现这些目标，他建立了一个前瞻性IPF队列， 进行连续采血，同时定量IPF进展速率。使用RNA和 随着疾病的发展，从IPF患者的血液淋巴细胞纵向收集DNA，他将整合 转录组模式与染色质特征，以确定容易获得的血细胞中的生物途径， 表示高风险IPF。从这些目标产生的数据将构成两个后续的基础 寻求验证基于血液的分子谱的独立提案， 快速进展的高风险，并探索和生物学验证表观遗传调控对 IPF病程背景下的基因表达模式和驱动途径。牛顿博士有一个 使用遗传和基因组标记预测高影响力转化研究的持续跟踪记录 肺纤维化的临床结局。这K23将使他获得必要的培训，以扩大他的 开发和验证新型生物标志物的技术技能和专业知识，构建临床有用的 预测模型，并整合下一代测序技术。他的指导团队由 在遗传学，表观遗传学，分子生物学， 生物信息学、统计学和IPF疾病行为。这K23是面向他的目标，成为一个 独立医生-科学家，其研究改善了IPF患者的临床护理。

PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is a devastating disorder of unknown etiology with a median survival of only 2-3 years. The rate of disease progression for individuals with IPF is highly variable. Rapid progression occurs in only 20-30% of patients but is responsible for 75% of IPF-related deaths. A major problem facing clinicians is that they are unable to identify patients that will experience rapid progression until after irreversible lung function decline occurs. Dr. Newton has previously demonstrated that pathogenic genetic variants in telomere- maintenance genes predispose to rapid progression; however, these static genetic variants alone do not explain the extreme heterogeneity in IPF clinical course. The variability in clinical course is strongly influenced by environmental exposures such as cigarette smoke or inflammation, which can alter chromatin structure and availability of gene regulatory elements, thus reprogramming gene expression profiles that produce divergent IPF disease course phenotypes. Therefore, Dr. Newton hypothesizes that integrating chromatin accessibility with gene expression will allow for the discovery of novel molecular markers and biologically relevant driver pathways that differentiate IPF disease course phenotypes. Along these lines, his Specific Aims are to 1) identify IPF patients at high-risk for short-term rapid progression using clinical, genomic, epigenetic, and gene expression signatures, 2) discover gene regulatory elements and biologic pathways that are associated with rapid IPF progression, and 3) identify changes in chromatin accessibility and gene expression that correspond to acute IPF exacerbations. To accomplish these aims, he has established a prospective IPF cohort designed to perform serial blood collection while simultaneously quantifying the rate of IPF progression. Using RNA and DNA from blood lymphocytes of IPF patients collected longitudinally as their disease evolves, he will integrate transcriptome patterns with chromatin features to identify biologic pathways in easily accessible blood cells that signify high-risk IPF. The data generated from these aims will form the foundation for two subsequent independent proposals that will seek to validate a blood-based molecular profile that identifies IPF patients at high-risk for rapid progression, and explore and biologically validate the influence epigenetic regulation on gene expression patterns and driver pathways within the context of IPF disease course. Dr. Newton has a sustained track record of high-impact translational research using genetic and genomic markers to predict clinical outcomes in pulmonary fibrosis. This K23 will allow him to obtain the necessary training to expand his technical skills and expertise in developing and validating novel biomarkers, constructing clinically useful prediction models, and integrating next-generation sequencing technologies. His mentoring team is composed of highly accomplished scientific mentors with expertise in genetics, epigenetics, molecular biology, bioinformatics, statistics, and IPF disease behavior. This K23 is geared toward his goal of becoming an independent physician-scientist whose research improves the clinical care of IPF patients.