Molecular Characterization of Progressive Pulmonary Sarcoidosis

进行性肺结节病的分子特征

• 批准号: 10582865
• 负责人: Maneesh Bhargava
• 金额: $ 82.67万
• 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: 2023-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582865
• 关键词: Address; Affect; Area; Automobile Driving; Bioinformatics; Biological; Biological Markers; Biology; Blood; Cells; Characteristics; Clinical; Clinical Management; Clinical Trials; Complex; Country; Cytometry; Data; Decision Making; Development; Disease; Disease Progression; Disease Resistance; Disease model; Early identification; Early treatment; Educational workshop; Enrollment; Event; FRAP1 gene; Foundations; Funding; Future; Gene Expression; Genes; Genetic Transcription; Goals; Granuloma; Granulomatous; Granulomatous disease; Health; Human; IL8 gene; In Vitro; Individual; Inflammation; Investigation; Knowledge; Laboratories; Link; Location; Lung; Lung nodule; Messenger RNA; Methods; Minnesota; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Natural Killer Cells; Ohio; Outcome; Pathologic; Pathway interactions; Patient Care; Patient Outcomes Assessments; Patients; Peripheral Blood Mononuclear Cell; Persons; Phagosomes; Phenotype; Plasma; Plasma Proteins; Population; Progressive Disease; Proteins; Proteomics; Proxy; Pulmonary Inflammation; Pulmonary Sarcoidosis; Research; Research Personnel; Research Priority; Respiratory Failure; Risk; Sampling; Sarcoidosis; Severities; Signal Transduction; Symptoms; Systems Biology; Testing; Therapeutic; Tissues; United States National Institutes of Health; Universities; Validation; Whole Blood; biological systems; body system; clinical decision-making; clinical trial enrollment; cohort; digital; disorder control; follow-up; follower of religion Jewish; genetic signature; high risk; improved; in vitro Model; innovation; insight; longitudinal care; mRNA Expression; molecular subtypes; mortality; novel; novel strategies; outcome prediction; predictive modeling; progression risk; prospective; protein expression; pulmonary function; recruit; single-cell RNA sequencing; targeted treatment; therapeutic target; tool; transcriptome sequencing; translational study

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.

项目概要 高达 90% 的结节病病例发生肺部受累，病程具有异质性且 在美国，呼吸衰竭是结节病相关死亡的主要原因。迄今为止进行的大多数研究 在结节病中，将病例与健康或疾病对照进行比较。认识上存在知识差距 结节病亚型，包括潜在的分子特征、生物学途径和机制 进行性肺结节病疾病进展。因此，没有可用于早期治疗的临床工具。 预测进行性 (P) 结节病，以便进行更密切的临床随访、早期治疗并提供重点 用于研究。该项目的目标是招募结节病患者以确定 P- 结节病将 (a) 能够及早识别进展风险较高的患者。开发工具 快速识别和预测 P-结节病进展，该项目将研究分子特征 （蛋白质和基因）以及结节病肉芽肿实验室模型中确定的相关生物学途径 以及 P- 与非进行性 (NP)- 结节病患者的外周血单核细胞 (PBMC) 的比较。 (二) 提供对驱动肺结节病结果的不同生物学机制的见解。我们的 有希望的试点数据确定了肉芽肿性炎症期间参与的蛋白质和转录途径 以及在 PMBC 中作为 P- 和 NP- 结节病的代表。目标 1 以初步发现为基础，描述了 利用独特的肉芽肿模型，研究 P- 和 NP- 结节病蛋白质和基因途径的差异。我们 使用创新的数字细胞计数方法在部分病例中进行单细胞 RNA 测序，以获得细胞 具体途径。目标 2 将定义 PBMC 的途径和签名，这些途径和签名是招募和贡献的 肉芽肿的发展和持续性以及与模型共有和不同的特征。目的 3 将利用创新技术利用 PMBC 的发现以及体外模型和临床疾病表现 生物信息学方法构建和内部验证综合分类器，其中包含 发现队列中的蛋白质、临床变量和患者报告的结果。调查人员将验证 该分类器位于先前 NIH 的研究团队已注册的独立验证队列中 资助的研究。该研究采用新颖的方法来表征 P-结节病和多元化的研究团队 由具有互补专业知识的 MPI 领导。来自不同地点的结节病调查人员的整合 全国各地将通过高度创新的转化来推进和维持结节病研究 在高度优先领域实施最先进的临床和生物系统级研究的研究 结节病研究。这些研究将为旨在评估这一点的未来研究奠定基础 纵向和患者护理研究中的分类器，以确定可能需要的高危结节病人群 更密切的随访和早期治疗，以及与识别新机制途径相关的研究 以及导致 P-结节病的治疗靶点。