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.

项目摘要 /摘要 结节病是一种多器官，免疫介导的炎症性疾病，具有高度可变的临床表现 和疾病课程。此外，在过去几十年中，结节病的死亡率似乎正在上升。 结节病的管理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作诊断的microRNA（miRNA） 生物标志物并将miRNA表达与结节病中的临床特征相关联 预后生物标志物。 生物标志物发展的基因组方法非常适合复杂的多基因疾病，例如 结节病，将成为该项目的重点。 miRNA作为结节病的生物标志物具有巨大的潜力 鉴于它们是表观遗传修饰剂和免疫反应调节剂的作用。在这笔赠款之前，我们进行了 在发现队列中完成的支气管肺泡灌洗（BAL）细胞样品上的miRNA测序 病例和健康对照；这个过程确定了7个不同表达的miRNA，我们将在所有 目前的提议的目的。在AIM 1中，我们将在验证中验证7个不同表达的miRNA 队列完成病例，健康对照和间质性肺部疾病控制。经过验证的miRNA 然后将作为结节病的诊断生物标志物进行测试。在AIM 2中，我们确定表达水平是否 在BAL时，这7种不同表达的miRNA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AIM 3中，我们将表征7种不同表达的miRNA的稳定性 在结节病病例的一部分中两年。这一发现以及AIM 2的结果将有助于 未来赠款中预后生物标志物的发展。 该提案将为林博士成为独立资助的长期目标提供坚实的基础 在转化结节病和环境/职业肺部研究领域的身体科学家。 特别是，该提案将继续建立她在基因组生物标志物开发方面的专业知识，纵向 研究设计和统计分析特定于结节病研究。该建议也将产生 她未来R01赠款提交的初步数据。