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）：该提案是对申请请求 RFA-12-013“AAT 缺乏症和结节病基因组研究 (GRADS)”的回应。作为从临床和研究角度来看，在结节病和 α-1 抗胰蛋白酶缺乏症 (AATD) 方面拥有丰富专业知识的中心，我们有能力招募本次 RFA 的患者和对照，并获得准确的表型分析并收集相关样本我们正在进行一项中心范围的研究。我们的研究人员在 RFA 的科学重点领域拥有专业知识，包括基因组学、免疫学/免疫表型分析和临床研究，这些将作为 U01 拨款的资源。本研究的目的是确定结节病和 AATD 这两种由遗传和环境相互作用引起的疾病的分子和免疫表型或特征。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 的差异免疫反应和免疫调节，并最终改变疾病表型和严重程度。第一个目标是作为一项在所有地点进行的研究范围提案，以确定结节病和 AATD 支气管肺泡灌洗细胞和外周血细胞与正常健康对照和吸烟引起的慢性阻塞性肺病对照的宿主先天和免疫分子谱。全基因组转录谱将用于定义分子谱，在病例比较中与对照相比，而且在病例比较研究中定义与疾病和更严重疾病形式相关的基因。建议对 BAL 微生物组进行评估，以进一步定义疾病和疾病表型的分子特征，因为疾病的微生物学病因很可能决定结节病的疾病表型，而微生物组则改变 AATD 的疾病表型。目标 2 和 3 将作为我们的临床特定地点方案，但将提供与研究的协同和整合。在目标 2 中，我们将确定结节病和 AATD 的肺部是否存在免疫调节缺陷或功能失调，重点关注疾病与对照和更严重疾病中的 T 调节细胞和 Th1/Th17 表型。该信息将提供重要的机制数据，但也可以作为免疫表型信息被研究范围的协议使用。最后，在目标 3 中，我们将整合目标 1 和 2 以及迄今为止的先前遗传学研究的信息，以定义决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位点。这些信息不仅将为 U01 研究范围的信息提供资源，而且可能对疾病诊断和预后产生影响，并为未来研究的治疗提供目标。相关性：结节病和 AATD 是导致高发病率和死亡率的罕见疾病。为什么有些人会患上这些疾病，而另一些人则不会，其自然史尚不清楚。该提案将定义可作为疾病生物标志物或预测因子，甚至最终需要治疗的因素。获得的数据将定义疾病和严重疾病的发病机制。最后，GRADS U01 的数据和信息将在公共领域提供，供其他研究人员用于未来疾病机制和易感性的研究。