MicroRNA as Diagnostic and Prognostic Biomarkers in Sarcoidosis

MicroRNA 作为结节病的诊断和预后生物标志物

• 批准号: 10664545
• 负责人: Nancy Weijiun Lin
• 金额: $ 18.25万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-05 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664545
• 关键词: Address; Affect; Biological Markers; Biopsy; Bronchoalveolar Lavage; Cause of Death; Cells; Characteristics; Clinical; Clinical Management; Cohort Studies; Complex; Data; Development; Diagnosis; Diagnostic Sensitivity; Disease; Disease Progression; Environment; Environmental Exposure; Epigenetic Process; Exclusion; Family; Foundations; Funding; Future; Genes; Genetic Predisposition to Disease; Genomic approach; Genomics; Goals; Grant; Granulomatous disease; Immune; Immune response; Individual; Inflammatory; Interstitial Lung Diseases; Intuition; Linear Regressions; Longitudinal Studies; Lung; Lung diseases; Mediating; Methods; MicroRNAs; Morbidity - disease rate; Occupational; Organ; Outcome; Pathogenesis; Pathway interactions; Peripheral Blood Mononuclear Cell; Persons; Physicians; Play; Process; Prognosis; Prognostic Marker; Pulmonary Sarcoidosis; Race; Research; Research Design; Resolution; Respiratory Failure; Role; Sampling; Sarcoidosis; Scientist; Sensitivity and Specificity; Severity of illness; Statistical Data Interpretation; System; Systemic disease; Testing; Time; Tissues; Untranslated RNA; Validation; Work; accurate diagnostics; biomarker development; caregiving; clinical care; clinical heterogeneity; cohort; diagnostic biomarker; differential expression; disorder control; genomic biomarker; improved; lung injury; miRNA expression profiling; microRNA biomarkers; mortality; next generation sequencing; prognostication; sex; skills

PROJECT SUMMARY / ABSTRACT Sarcoidosis is a multi-organ, immune-mediated inflammatory disease with a highly variable clinical presentation and disease course. Additionally, the mortality rate from sarcoidosis appears to be rising over the past decades. A significant challenge in the management of sarcoidosis is the lack of reliable diagnostic and prognostic biomarkers. The objective of this project is to define microRNAs (miRNAs) that can be used as diagnostic biomarkers and to associate miRNA expression with clinical characteristics in sarcoidosis for the development of prognostic biomarkers. A genomic approach to biomarker development is well suited for complex, polygenetic diseases such as sarcoidosis and will be the focus of this project. miRNAs have significant potential as biomarkers in sarcoidosis given their role as epigenetic modifiers and immune response regulators. Prior to this grant, we performed miRNA sequencing on bronchoalveolar lavage (BAL) cell samples in a discovery cohort comprised of sarcoidosis cases and healthy controls; this process identified 7 differentially expressed miRNAs, which we will use in all the aims of this current proposal. In Aim 1, we will validate the 7 differentially expressed miRNAs in a validation cohort comprised of cases, healthy controls, and interstitial lung disease controls. The miRNAs that are validated will then be tested as a diagnostic biomarker for sarcoidosis. In Aim 2, we determine if the expression levels of the 7 differentially expressed miRNAs at the time of BAL reflect clinical manifestations of sarcoidosis. We will also determine if the miRNA expression levels at the time of BAL can predict changes in clinical manifestations over two years. Finally, in Aim 3, we will characterize the stability of the 7 differentially expressed miRNAs over two years in a subset of sarcoidosis cases. This finding, along with the results from Aim 2, will help in the development of prognostic biomarkers in a future grant. This proposal will provide a strong foundation for Dr. Lin’s long-term goal of becoming an independently funded physician-scientist in the field of translational sarcoidosis and environmental/occupational pulmonary research. Specifically, this proposal will continue to build her expertise in genomic biomarker development, longitudinal study design, and statistical analyses specific to sarcoidosis research. This proposal will also generate preliminary data for her future R01 grant submissions.

项目总结/摘要 结节病是一种多器官、免疫介导的炎症性疾病，临床表现多变 和病程。此外，结节病的死亡率在过去几十年中似乎在上升。 结节病治疗中的一个重大挑战是缺乏可靠的诊断和预后 生物标志物。该项目的目的是定义可用于诊断的microRNAs（miRNAs）。 生物标志物，并将miRNA表达与结节病的临床特征联系起来， 预后生物标志物。 生物标志物开发的基因组方法非常适合于复杂的多基因疾病，如 结节病，并将成为该项目的重点。miRNAs作为结节病的生物标志物具有重要的潜力 鉴于它们作为表观遗传修饰剂和免疫应答调节剂的作用。在此之前，我们进行了 结节病发现队列中支气管肺泡灌洗（BAL）细胞样本的miRNA测序 病例组和健康对照组;该过程鉴定了7种差异表达的miRNAs，我们将在所有的 目前这项提案的目的。在目标1中，我们将在验证中验证7个差异表达的miRNAs， 队列由病例、健康对照和间质性肺病对照组成。验证过的miRNAs 将作为结节病的诊断生物标志物进行测试。在目标2中，我们确定是否表达水平 BAL时差异表达的7种miRNAs反映了结节病的临床表现。我们将 还确定BAL时的miRNA表达水平是否可以预测临床表现的变化 超过两年。最后，在目标3中，我们将描述7种差异表达的miRNAs的稳定性， 在结节病病例的一个亚组中两年。这一发现，沿着目标2的结果，将有助于 在未来的补助金中开发预后生物标志物。 这一建议将为林博士成为一个独立资助的长期目标奠定坚实的基础。 转化结节病和环境/职业肺研究领域的医生-科学家。 具体来说，这项建议将继续建立她在基因组生物标志物开发，纵向 研究设计和结节病研究的统计分析。该提案还将产生 为她未来的R 01资助申请提供初步数据。