Molecular Markers of Idiopathic Pulmonary Fibrosis Progression

特发性肺纤维化进展的分子标志物

• 批准号: 9976056
• 负责人: Chad Alan Newton
• 金额: $ 17.82万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9976056
• 关键词: Acute; Architecture; Automobile Driving; Behavior; Bioinformatics; Biological; Biological Assay; Blood; Blood Cells; Cessation of life; Chromatin; Chromatin Structure; Clinical; Clinical Data; Collection; DNA; Data; Disease; Disease Progression; Dyspnea; Enrollment; Environment; Environmental Exposure; Epigenetic Process; Etiology; Expression Profiling; Fibrosis; Foundations; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic; Genetic Markers; Genomics; Goals; Heterogeneity; Hypoxemia; Impairment; Individual; Inflammation; Light; Lung diseases; Lymphocyte; Medical Genetics; Mentors; Molecular; Molecular Biology; Molecular Profiling; Outcome; Pathogenicity; Pathway interactions; Patients; Pattern; Phenotype; Physicians; Pulmonary Fibrosis; Pulmonology; RNA; Regulation; Regulator Genes; Regulatory Element; Research; Research Personnel; Respiratory physiology; Risk; Scientist; Susceptibility Gene; Technical Expertise; Technology; Telomere Maintenance Gene; Testing; Training; Translational Research; Transposase; Vital capacity; base; cigarette smoke; clinical care; cohort; design; disorder risk; epigenetic regulation; experience; gene discovery; genetic variant; genomic biomarker; high risk; idiopathic pulmonary fibrosis; improved; innovation; molecular marker; next generation sequencing; novel; novel marker; personalized management; predict clinical outcome; predictive modeling; prospective; statistics; telomere; tool; transcriptome; transcriptome sequencing; translational impact

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.

项目总结 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患者的疾病进展速度具有很高的变异性。进展迅速 仅在20%-30%的患者中发生，但在75%的IPF相关死亡中负有责任。临床医生面临的一个主要问题是 他们无法确定在不可逆转的肺脏之后才会经历快速进展的患者 出现功能衰退。牛顿博士此前曾证明，端粒中的致病基因变异-- 维持基因易于快速进展；然而，这些静态的遗传变异本身并不能 解释IPF临床过程中的极端异质性。临床病程的可变性受到很大影响。 暴露在环境中，如香烟烟雾或炎症，可以改变染色质结构和 基因调控元件的可用性，从而对产生差异的基因表达谱进行重新编程 IPF病程表型。因此，牛顿博士假设，将染色质的可及性 基因表达将有助于发现新的分子标记和生物相关的驱动因素 区分IPF病程表型的途径。按照这些思路，他的具体目标是1) 利用临床、基因组、表观遗传学和基因识别IPF患者短期快速进展的高风险 表达特征，2)发现与以下相关的基因调控元件和生物途径 快速的IPF进展，以及3)确定染色质可及性和相应的基因表达的变化 到IPF的急性加重。为了实现这些目标，他建立了一个预期的IPF队列 进行连续采血，同时量化IPF的进展速度。使用RNA和 随着疾病的发展，纵向收集的IPF患者血淋巴细胞的DNA，他将整合 带有染色质特征的转录组模式，以识别易于访问的血细胞中的生物途径 标志着高风险的IPF。从这些目标产生的数据将构成随后的两个 独立的提案将寻求验证基于血液的分子档案，以识别IPF患者 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的翻译研究的持续跟踪记录 肺纤维化的临床转归。这将使他能够获得必要的培训，以扩大他的 开发和验证新的生物标志物，构建临床有用的技术技能和专业知识 预测模型，并集成下一代测序技术。他的指导团队是由 拥有遗传学、表观遗传学、分子生物学等专业知识的高水平科学导师， 生物信息学、统计学和IPF疾病行为。这款K23是为了实现他成为一名 独立内科医生-科学家，他的研究改善了IPF患者的临床护理。