Molecular and Cellular Determinants of Disease Heterogeneity in COPD

描述（由申请人提供）： 匹兹堡大学COPD SCORR建立在我们长期研究慢性阻塞性肺疾病的传统基础上，提出了四个项目提案，扩展了我们以前的工作以及我们与不列颠哥伦比亚省大学的密切合作。在项目1中，COPD表型异质性的外周标志物;我们的总体假设：COPD是一组可定义的解剖学和生理学疾病过程的异质性，每种疾病过程都有其自身的分子和细胞过程，决定疾病表现和进展;这将在800例患者的充分表征队列中进行测试。在项目2中，COPD中的适应性免疫诱导的气道损伤，我们假设由同源识别和对肽抗原的应答驱动的适应性免疫过程引起或促成导致COPD进展的气道损伤;这将主要在人肺外植体中进行测试。在项目3 EGR-1中：我们将把人体组织实验的结果转化为小鼠模型，以确定早期生长反应（EGR-1）是否在香烟烟雾诱导的慢性阻塞性肺疾病（COPD）的背景下调节细胞凋亡和炎症途径的协调表达。在项目4中，COPD气雾剂免疫疗法的临床研究中，我们假设用特定生物制剂调节COPD受试者中鉴定的免疫应答将消除或改善致病机制并改变COPD的自然病程。

DESCRIPTION (provided by applicant): The University of Pittsburgh SCORR in COPD builds upon our long tradition of research in Chronic Obstructive Pulmonary Disease to propose a four project proposal which extends our previous work and our strong collaboration with the University of British Columbia. In project 1 Peripheral Markers of Phenotypic Heterogeneity in COPD; Our global hypothesis: COPD is a heterogeneous group of definable anatomic and physiologic disease processes, each with its own molecular and cellular processes that determine disease manifestation and progression; this will be tested in a well characterized cohort of 800 patients. In project 2 Adaptive Immune-Induced Airway Injury in COPD, we postulate that adaptive immune processes, driven by cognate recognition and responses to peptide antigens, cause or contribute to the airway injuries that result in COPD progression; this will be tested largely in human lung explants. In project 3 EGR-1: Regulator Of Apoptosis And Inflammation in COPD we will translate results from human tissue experiments into mouse models to determine whether early growth response (EGR-1), regulates the coordinated expression of apoptosis and inflammation pathways in the context of cigarette smoke-induced chronic obstructive pulmonary disease (COPD). In project 4 Clinical Investigation Of Aerosol Immunotherapy in COPD we hypothesize that modulation of identified immune responses in COPD subjects with specific biologic agents will ablate or ameliorate pathogenic mechanisms and alter the natural history of COPD.