GRADS Cooperative Research Project: JHU Clinical Center

GRADS 合作研究项目：JHU 临床中心

基本信息

批准号：
8464252
负责人：
David R Moller
金额：
$ 15.61万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8464252
关键词：
Acute-Phase Proteins Affect Amyloid Amyloid beta-Protein Precursor Antigens Biological Assay Biological Markers Biopsy Blood Blood Cells Blood specimen Body part Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid CD4 Positive T Lymphocytes Cells Cessation of life Chronic Clinic Clinical Collagen DNA Data Diagnosis Diagnostic tests Disease Disorder by Site Etiology Fibrosis Gene Expression Genes Genetic Genomics Giant Cells Goals Granuloma Granulomatous Health Heat shock proteins Heterogeneity Host Defense IL18 gene Immune response Immunity Immunobiology Immunohistochemistry Immunologics Immunophenotyping Incidence Individual Infection Infiltration Inflammation Inflammatory Interleukin-12 Japan Laboratories Leadership Link Lung Measures Mediating Mediator of activation protein Metalloproteases Molecular Abnormality Mononuclear Mycobacterium Infections Newly Diagnosed Nodule Organ Organism Outcome Pathologic Pathway interactions Patients Pattern Peptides Peripheral Blood Mononuclear Cell Peroxidases Phenotype Positioning Attribute Production Progressive Disease Proteins Proteomics Protocols documentation Pulmonary Fibrosis Relative (related person)Reporting Research Project Grants Risk Role Sampling Studies Sarcoidosis Serum amyloid A protein Severities Staging Staining method Stains Stratification Structure of parenchyma of lung T cell response T-Cell Receptor T-Lymphocyte TNF gene Tissue Sample Tissues Toll-Like Receptor 2 Toll-like receptors Up-Regulation Whole Blood alpha 1-Antitrypsin Deficiency base catalase chemokine clinical phenotype cytokine disease characteristic effective therapy enzyme linked immunospot assay experience health disparity killings microbial microorganism antigen mycobacterial novel novel therapeutic intervention outcome forecast receptor response

项目摘要

DESCRIPTION (provided by applicant): Sarcoidosis and Alpha-1 Antitrypsin Deficiency are uncommon, understudied diseases that lack safe, effective treatments. Sarcoidosis is a multisystem granulomatous disorder that involves the lungs in over 90% of affected individuals and may cause end-stage pulmonary fibrosis and death. With an incidence of ~10-40 per 100,000 people in the U.S., sarcoidosis represents a significant health problem and health disparity concern. The pathologic hallmarks of sarcoidosis are non-caseating granulomas and polarized Th1 immunity at sites of disease. There is tremendous clinical heterogeneity with respect to organ involvement, severity and clinical course with both remitting and chronic progressive disease. There are no diagnostic tests for sarcoidosis except for biopsy of affected tissues, and no clinically useful biomarkers for risk stratification, prognosis or response to treatment. The goals of the study are to identify molecular abnormalities and their relationship to disease characteristics by employing genomics and microbiomics analyses of systematically phenotyped subjects, and to elucidate pathogenic mechanisms and identify predictors of disease. Proposed Aim 1 studies will systematically phenotype newly diagnosed sarcoidosis patients and provide lung, blood and tissue samples for study wide genomic and microbiomic analyses. Study-wide protocols will be established to evaluate the antigen specific immune responses to candidate pathogenic microbial antigens in sarcoidosis and correlate these dynamic measures with clinical phenotype and genomic/microbiomic analyses. Proposed Aim 2 studies will explore the hypothesis that serum amyloid A, an acute phase reactant and amyloid precursor protein, is a central mediator of chronic inflammation and fibrosis by correlating SAA levels in blood, lung and tissues with clinical phenotype and genomic/microbiomic analyses, assessing the proinflammatory and profibrotic cytokine-inducing effects of SAA on blood and lung cells in sarcoidosis, and identifying the receptor pathways that mediate these effects. These studies may establish links between specific clinical phenotypes, microbial etiologies, and common pathogenic mechanisms to provide a framework for new therapeutic approaches to sarcoidosis.

描述（由申请人提供）：结节症和α-1抗胰蛋白酶缺乏症并不常见，研究的疾病缺乏安全，有效的治疗方法。结节病是一种多系统肉芽肿性疾病，涉及超过90％的受影响个体的肺部，可能导致终末期肺纤维化和死亡。在美国，每100,000人的发生率约为10-40人，结节病代表着重大的健康问题和健康差异。结节病的病理标志是疾病部位的无造成肉芽肿和极化的Th1免疫。关于器官的参与，严重程度和临床病程具有巨大的临床异质性，并具有恢复性和慢性进行性疾病。除了受影响组织的活检外，没有针对结节病的诊断测试，也没有用于风险分层，预后或对治疗反应的临床有用的生物标志物。该研究的目标是通过采用基因组学和微生物组学分析系统表型受试者，并阐明致病机制并确定疾病的预测因素，以鉴定分子异常及其与疾病特征的关系。拟议的目标1研究将系统地从系统地表型新诊断的结节病患者，并提供肺，血液和组织样本，用于研究广泛的基因组和微生物分析。将建立研究范围的方案，以评估结节病中抗原特异性免疫反应对候选病原微生物抗原的特异性免疫反应，并将这些动态测量与临床表型和基因组/微生物分析相关联。 Proposed Aim 2 studies will explore the hypothesis that serum amyloid A, an acute phase reactant and amyloid precursor protein, is a central mediator of chronic inflammation and fibrosis by correlating SAA levels in blood, lung and tissues with clinical phenotype and genomic/microbiomic analyses, assessing the proinflammatory and profibrotic cytokine-inducing effects of SAA on blood and lung cells在结节病中，并鉴定介导这些作用的受体途径。这些研究可能在特定的临床表型，微生物病因和常见致病机制之间建立联系，以为新的治疗方法提供结节病的框架。