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.

项目摘要 高达90%的结节病病例发生肺部受累，病程不均匀， 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。在理解上存在知识差距 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，没有可用于早期诊断的临床工具。 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，这将（a）使得能够早期识别处于更高进展风险的患者。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 在结节病肉芽肿的实验室模型中鉴定的（蛋白质和基因）和相关生物学途径 和外周血单个核细胞（PBMC）的P-与非进展性（NP）-结节病患者。（B） 提供了不同的生物学机制驱动肺结节病的结果的见解。我们 有希望的试点数据确定蛋白质和转录途径参与肉芽肿性炎症 PMBCs中的P-和NP-结节病的替代物。目标1建立在初步调查结果的基础上， P-和NP-结节病蛋白和基因通路的差异，利用独特的肉芽肿模型。我们 包括在一部分病例中使用创新数字细胞术方法进行单细胞RNA测序， 具体路径。目标2将定义来自PBMC的途径和特征，这些途径和特征被招募并有助于 肉芽肿的发展和持久性以及与模型共享和不同的特征。目的 3将利用来自PMBC的发现和体外模型以及使用创新的 生物信息学方法来构建和内部验证综合分类器， 蛋白质、临床变量和患者报告的结果。调查人员将确认 该分类器在一个独立的验证队列中的受试者已经被研究小组在先前的NIH中招募 资助的研究。这项研究使用了新的方法来描述P-结节病和一个多样化的研究团队 由具有互补专业知识的MPI领导。来自不同地区的结节病研究者的整合 全国各地将通过高度创新的翻译， 在以下高度优先领域开展最先进的临床和生物系统水平研究： 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。 分类器在纵向和患者护理研究，以确定一个风险结节病人群，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 和有助于P-结节病的治疗靶标。