GRADS Cooperative Research Project: JHU Clinical Center

GRADS 合作研究项目：JHU 临床中心

• 批准号: 8662311
• 负责人: David R Moller
• 金额: $ 16.07万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662311
• 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

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)： 结节病和Alpha-1抗胰蛋白酶缺乏症是一种罕见的、研究不足的疾病，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，90%以上的患者累及肺部，可能导致终末期肺纤维化和死亡。在美国，结节病的发病率约为每10万人10-40人，是一个重大的健康问题和健康差距问题。结节病的病理特征是非干酪性肉芽肿和发病部位Th1免疫极化。缓解性和慢性进展性疾病在器官受累、严重程度和临床病程方面存在巨大的临床异质性。除了病变组织的活检，没有结节病的诊断测试，也没有临床上有用的生物标志物来进行风险分层、预后或对治疗的反应。这项研究的目的是通过对系统表型受试者进行基因组学和微生物学分析，识别分子异常及其与疾病特征的关系，并阐明致病机制和确定疾病的预测因素。拟议的Aim 1研究将系统地对新诊断的结节病患者进行表型分析，并为研究广泛的基因组和微生物学分析提供肺、血液和组织样本。将建立广泛的研究方案来评估结节病患者对候选致病微生物抗原的抗原特异性免疫反应，并将这些动态指标与临床表型和基因组/微生物分析相关联。拟议的AIM 2研究将通过将血液、肺和组织中的SAA水平与临床表型和基因组/微生物分析相关联，评估SAA对结节病患者血液和肺细胞的促炎和促纤维化细胞因子的诱导作用，并确定介导这些影响的受体途径，来探讨血清淀粉样蛋白A是一种急性时相反应物和淀粉样前体蛋白是慢性炎症和纤维化的中心介质的假设。这些研究可能会建立特定的临床表型、微生物病因和常见致病机制之间的联系，为结节病的新治疗方法提供一个框架。