Molecular Characterization of Progressive Pulmonary Sarcoidosis

项目总结 高达90%的结节病病例会累及肺部，其病程是不同的， 呼吸衰竭是美国结节病相关死亡的主要原因。到目前为止进行的大多数研究 在结节病方面，将病例与健康或疾病对照进行比较。在理解上存在着知识鸿沟 结节病亚型的基本分子特征、生物学途径和发病机制 进行性肺结节病疾病进展。因此，目前尚无临床工具可用于早期治疗。 预测进行性(P)结节病，以便进行更密切的临床随访、早期治疗和提供病灶 用于研究。本项目的目标是招募结节病患者以确定P-P-1的分子特征。 结节病将(A)能够及早发现进展风险较高的患者。为以下项目开发工具 快速鉴定和预测P-结节病的进展，本项目将研究分子特征 结节病肉芽肿实验室模型中确定的(蛋白质和基因)和相关生物途径 P-VS非进行性(NP)结节病患者外周血单个核细胞(PBMC)。(B) 提供对肺结节病不同生物学机制结果的洞察。我们的 有希望的试点数据确定了肉芽肿性炎症过程中参与的蛋白质和转录途径 P结节病和NP结节病的代用品中的PMBC也有表达。目标1建立在初步发现的基础上，表征 P-和NP-结节病蛋白和基因途径的差异，利用独特的肉芽肿模型。我们 包括利用创新数字细胞术方法在病例子集中进行单细胞RNA测序，以获得细胞- 特定的路径。目标2将定义来自PBMC的路径和签名，这些路径和签名被招募并贡献 到肉芽肿的发展和持久性以及与模型共享和不同的功能。目标 3将利用PMBC的研究结果以及体外模型和临床疾病表现，使用创新的 构建和内部验证综合分类器的生物信息学方法 发现队列中的蛋白质、临床变量和患者报告的结果。调查人员将确认 这个分类器在一个独立的验证队列中的受试者中已经被先前的NIH研究团队登记 资助的研究。这项研究使用了新的方法来表征P-结节病和一个不同的研究团队 由具有互补专业知识的MPI领导。整合来自不同地点的结节病调查人员 全国各地将通过高度创新的翻译来推进和维持结节病的研究 在高优先级领域实施最先进的临床和生物系统水平研究的研究 结节病的研究。这些研究将为未来旨在评估这一点的研究提供基础 纵向和患者护理研究中的分类器，以识别可能需要 更密切的随访和早期治疗，以及与识别新的机制途径有关的研究 以及导致P-结节病的治疗靶点。

PROJECT SUMMARY Pulmonary involvement occurs in up to 90% of sarcoidosis cases, the disease course is heterogeneous and respiratory failure is the leading cause of sarcoidosis-related mortality in the US. Most studies undertaken to date in sarcoidosis compare cases to healthy or disease controls. There are knowledge gaps in the understanding of sarcoidosis subtypes including the underlying molecular features, biologic pathways and mechanisms of progressive pulmonary sarcoidosis disease progression. As a result, there are no clinical tools available for early prediction of progressive (P) sarcoidosis to allow closer clinical follow-up, early treatment and to provide focus for research. The goal of this project is to enroll sarcoidosis patients to define molecular characteristics of P- sarcoidosis that will (a) enable early identification of patients at higher risk of progression. To develop tools for rapid identification and prediction of P-sarcoidosis progression, this project will investigate molecular signatures (proteins and genes ) and related biological pathways identified in a laboratory model of sarcoidosis granulomas and in peripheral blood mononuclear cells (PBMCs) of patients with P- vs non-progressive (NP)- sarcoidosis. (b) provide insights into the different biological mechanisms driving outcomes in pulmonary sarcoidosis. Our promising pilot data identified protein and transcriptional pathways engaged during granulomatous inflammation and in PMBCs in proxies of P- and NP-sarcoidosis. Aim 1 builds on preliminary findings, characterizing differences in P- and NP-sarcoidosis protein and gene pathways, leveraging the unique granuloma model. We include single cell-RNA-Sequencing in a subset of cases with innovative digital cytometry methods to obtain cell- specific pathways. Aim 2 will define pathways and signatures from PBMCs, which are recruited and contribute to granuloma development and persistence as well as features that are shared and distinct from the model. Aim 3 will leverage findings from PMBCs and the in vitro model and clinical disease manifestations using innovative bioinformatics approaches to construct and internally validate a comprehensive classifier that incorporates proteins, clinical variables and patient-reported outcomes in a Discovery Cohort. The investigators will validate this classifier in an independent Validation Cohort of subjects already enrolled by the research team in prior NIH funded studies. The study uses novel approaches to characterize P-sarcoidosis and a diverse research team led by MPIs with complementary expertise. The integration of sarcoidosis investigators from different locations across the country will advance and sustain the sarcoidosis research through highly innovative translational studies implementing state-of-the-art clinical and biological systems-level studies in a high-priority area of research in sarcoidosis. These studies will provide the foundation for future studies aimed at evaluating this classifier in longitudinal and patient care studies to identify an at-risk sarcoidosis population that may require closer follow up and earlier treatment, and research pertaining to the identification of novel mechanistic pathways and therapeutic targets contributing to P-sarcoidosis.