Immunologic and Molecular Phenotypes in AATD and Sarcoidosis

AATD 和结节病的免疫学和分子表型

• 批准号: 8662308
• 负责人: LISA A MAIER
• 金额: $ 15.53万
• 依托单位: NATIONAL JEWISH HEALTH
• 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/8662308
• 关键词: Address; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autoimmune Process; Biological Markers; Blood; Blood Cells; Breathing; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; Case-Control Studies; Cell Proliferation; Cells; Chronic Obstructive Airway Disease; Clinical Research; Communities; Data; Development; Disease; Enrollment; Environment; Environmental Risk Factor; Etiology; Evaluable Disease; Evaluation; Exposure to; Future; Genes; Genetic; Genetic Determinism; Genetic Transcription; Genomics; Genus Mycobacterium; Goals; Grant; Granulomatous; Hand; Health; Immune; Immune response; Immunogenetics; Immunologics; Immunology; Immunophenotyping; Infection; Inflammation; Inflammatory; Informatics; Lung; Medicine; Molecular; Molecular Profiling; Morbidity - disease rate; Natural History; Occupational Exposure; Organ; Pathogenesis; Pathologic; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Predisposition; Production; Protease Inhibitor; Proteins; Proteolysis; Protocols documentation; Public Domains; Pulmonary Emphysema; Pulmonary Sarcoidosis; Rare Diseases; Recruitment Activity; Regulation; Regulatory T-Lymphocyte; Request for Applications; Research; Research Personnel; Research Project Grants; Resources; Respiratory Tract Infections; Respiratory physiology; Risk; Risk Factors; Role; Sampling; Sarcoidosis; Serine Protease; Severities; Severity of illness; Site; Smoking; Specialized Center; Specimen; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Trypsin; U-Series Cooperative Agreements; Work; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; base; chemokine; cigarette smoking; cigarette smoking; clinical care; clinical research site; cost; cytokine; disease diagnosis; disease mechanisms study; disease phenotype; disorder risk; follower of religion Jewish; genetic risk factor; genome-wide; immunoregulation; macrophage; microbiome; molecular phenotype; monocyte; mortality; novel; polymerization; protective effect; respiratory; response

DESCRIPTION (provided by applicant): This proposal is in response to the request for application, RFA-12-013, "Genomic Research in AAT-Deficiency and Sarcoidosis study (GRADS)". As a center with significant expertise in sarcoidosis and alpha- 1 anti-trypsin deficiency (AATD) from a clinical and research standpoint, we have the ability to recruit patients and controls for this RFA as well as obtain accurate phenotyping and to collect relevant specimens for us in a center-wide study. Our investigators have expertise in the scientific focus of the RFA, including genomics, immunology/immunophenotyping, and clinically based research, which would serve as a resource for this U01 grant. The goal of this study is to define the molecular and immunologic phenotype or signature of sarcoidosis and AATD, two diseases that result from genetic and environmental interaction. Based on this information we propose three aims to address our hypothesis that key immune genes and pathways result in differential immune response and immune modulation in both sarcoidosis and AATD and ultimately modify disease phenotype and severity. The first aim is proposed as a study-wide proposal, to be conducted at all sites, to define the host innate and immune molecular profile in sarcoidosis and AATD bronchoalveolar lavage cells and peripheral blood cells compared to normal healthy controls and smoking-induced COPD controls. Genome-wide transcription profiles would be used to define the molecular profiles, in cases-compared to controls, but also in a case-comparison study to define the genes associated with disease and more severe forms of disease. Evaluation of BAL microbiome is proposed to further define the molecular profiles of disease and disease phenotype, as it is likely that microbiologic etiology of disease determines disease phenotype in sarcoidosis, while the microbiome modifies disease phenotype in AATD. Aims 2 and 3 will serve as our clinical site-specific protocol, but will provide synergy and integration with the study-wid research. In Aim 2, we will determine if there is a deficient or dysfunctional immune regulation occurring in the lung of sarcoidosis and AATD, focusing on T-regulatory cells and Th1/Th17 phenotype, in disease compared to controls and in more severe disease. This information will provide important mechanistic data, but also be evaluable for use by the study-wide protocols as immunophentoyping information. Finally, in Aim 3, we will integrate information from Aims 1 and 2 and from prior genetic studies to date to define genetic determinants and expression quantitative loci that determine the immunogenomic response in disease and modify disease severity. This information will not only provide a resource to the U01 study-wide information, but information that may have implications in disease diagnosis and prognois and provide targets for therapies for future study. RELEVANCE: Sarcoidosis and AATD are rare diseases that result in significant morbidity and mortality. The reason why some develop these diseases and others do not and the natural history is not well understood. This proposal will define factors that may serve as biomarkers or predictors of disease and ultimately even need for therapy. The data derived will define pathogenetic mechanisms of disease and severe disease. Finally, the data and information for the GRADS U01 that will be available in the public domain to be used by other investigators for future study of disease mechanisms and susceptibility.

描述（由申请人提供）： 本提案是对申请RFA-12-013“AAT缺乏症和结节病研究（GRADS）中的基因组研究”的回应。从临床和研究角度来看，作为一家在结节病和α-1抗胰蛋白酶缺乏症（AATD）方面具有丰富专业知识的中心，我们有能力招募患者和对照进行该RFA，并获得准确的表型，并在全中心研究中为我们收集相关标本。我们的研究人员在RFA的科学重点方面具有专业知识，包括基因组学，免疫学/免疫表型和临床研究，这将作为U 01赠款的资源。本研究的目的是确定结节病和AATD的分子和免疫学表型或特征，这两种疾病是遗传和环境相互作用的结果。基于这些信息，我们提出了三个目标来解决我们的假设，即关键免疫基因和途径导致结节病和AATD的差异免疫应答和免疫调节，并最终改变疾病表型和严重程度。第一个目的是作为一项研究范围内的建议，在所有研究中心进行，以确定与正常健康对照和吸烟诱导的COPD对照相比，结节病和AATD支气管肺泡灌洗液细胞和外周血细胞中的宿主先天性和免疫分子特征。全基因组转录谱将被用于定义分子谱，在病例中与对照相比，但也在病例比较研究中定义与疾病和更严重形式的疾病相关的基因。建议对BAL微生物组进行评价，以进一步确定疾病和疾病表型的分子特征，因为疾病的微生物病因可能决定结节病的疾病表型，而微生物组改变AATD的疾病表型。目标2和3将作为我们的临床研究中心特定方案，但将提供与研究范围研究的协同作用和整合。在目标2中，我们将确定结节病和AATD的肺中是否存在免疫调节缺陷或功能失调，重点关注T调节细胞和Th 1/Th 17表型，与对照组和更严重的疾病相比。该信息将提供重要的机制数据，但也可作为免疫表型信息用于研究范围的方案。最后，在目标3中，我们将整合来自目标1和2以及迄今为止的遗传学研究的信息，以定义决定疾病免疫基因组学应答和改变疾病严重程度的遗传决定因素和表达定量基因座。这些信息不仅将为U 01研究范围内的信息提供资源，而且还将提供可能对疾病诊断和预后有影响的信息，并为未来研究的治疗提供目标。 相关性：结节病和AATD是导致显著发病率和死亡率的罕见疾病。为什么有些人发展这些疾病和其他人没有和自然历史的原因还没有得到很好的理解。该提案将定义可能作为疾病生物标志物或预测因子的因素，甚至最终需要治疗。所得到的数据将确定疾病和严重疾病的发病机制。最后，GRADS U 01的数据和信息将在公共领域提供给其他研究人员用于未来的疾病机制和易感性研究。