Immunologic and Molecular Phenotypes in AATD and Sarcoidosis

AATD 和结节病的免疫学和分子表型

基本信息

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
项目类别：
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

项目摘要

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）：该提案是对应用要求，RFA-12-013的要求，“ AAT缺乏和结节病研究（GRADS）的基因组研究”。从临床和研究的角度来看，作为在结节病和α-1抗肌蛋白缺乏症（AATD）方面具有重要专业知识的中心，我们有能力在中心研究中招募患者和对照，并获得准确的表型并为我们收集相关的标本。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/免疫表型和基于临床的研究，这将是该U01赠款的资源。这项研究的目的是定义遗传和环境相互作用引起的两种疾病的结节病和AATD的分子和免疫表型或特征。基于这些信息，我们提出三个旨在解决我们的假设，即关键免疫基因和途径会导致结节病和AATD的免疫反应和免疫调节，并最终改变疾病的表型和严重性。第一个目的是作为在所有部位进行的研究范围内提出的，以定义结节病和AATD支气管肺泡灌洗细胞和外周血细胞中的宿主先天和免疫分子特征，并与正常的健康对照和吸烟诱导的COPD对照相比。全基因组的转录曲线将用于定义分子谱，在对照组合的病例中，以及在一项病例比较的研究中，以定义与疾病和更严重的疾病相关的基因。提出了对BAL微生物组的评估来进一步定义疾病和疾病表型的分子特征，因为疾病的微生物病因学可能决定了结节症中的疾病表型，而微生物组可能会改变AATD中的疾病表型。 AIM 2和3将作为我们临床特定地点方案，但将与研究WID研究相结合。在AIM 2中，我们将确定与对照组和更严重的疾病相比，在结节病和AATD的肺中是否存在缺乏或功能失调的免疫调节，重点是T-调节细胞和TH1/TH17表型。该信息将提供重要的机械数据，但也可以评估用于整个研究方案作为免疫注射信息。最后，在AIM 3中，我们将从AIM 1和1和先前的遗传研究中整合信息，以定义确定疾病中免疫基因组反应并改变疾病严重程度的遗传决定因素和表达定量基因座。该信息不仅将为U01学习范围的信息提供资源，而且可能对疾病诊断和预后有影响，并为未来研究的疗法提供目标。相关性：结节病和AATD是罕见的疾病，导致发病率明显和死亡率。有些人出现这些疾病而其他人没有的原因，自然史没有很好地理解。该提案将定义可能是疾病的生物标志物或预测因素，甚至最终需要治疗的因素。得出的数据将定义疾病和严重疾病的致病机制。最后，将在公共领域中可用的毕业生U01的数据和信息可供其他研究人员使用，以将来研究疾病机制和易感性。