MicroRNA as Diagnostic and Prognostic Biomarkers in Sarcoidosis

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，临床表现多变。 和病程。此外，在过去的几十年里，结节病的死亡率似乎在上升。 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。该项目的目标是定义可用于诊断的microRNAs(miRNAs 结节病的生物标志物及miRNA表达与临床特征的关系 预后生物标记物。 生物标记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，并将是这一项目的重点。MiRNAs作为结节病生物标志物的潜力很大 考虑到它们作为表观遗传调节剂和免疫反应调节器的作用。在这笔赠款之前，我们进行了 在发现结节病的队列中对支气管肺泡灌洗(BAL)细胞样本进行miRNA测序 病例和健康对照；这个过程确定了7个差异表达的miRNAs，我们将在所有 这项当前提案的目的。在目标1中，我们将在验证中验证7个差异表达的miRNA 队列由病例、健康对照和间质性肺疾病对照组成。经过验证的miRNAs 然后将被测试为结节病的诊断生物标记物。在目标2中，我们确定是否表达水平 BAL时差异表达的7个miRNAs反映了结节病的临床表现。我们会 同时确定BAL时miRNA的表达水平是否可以预测临床表现的变化 两年多了。最后，在目标3中，我们将表征7个差异表达的miRNAs在 在结节病病例中有两年的时间。这一发现，以及AIM 2的结果，将有助于 未来拨款中预测生物标记物的发展。 这项提议将为林博士成为独立资助的 转化性结节病和环境/职业性肺部研究领域的内科科学家。 具体地说，这项提议将继续积累她在基因组生物标记物开发方面的专业知识，纵向 研究设计，针对结节病研究的统计分析。这项提议还将产生 她未来R01拨款申请的初步数据。

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.