The overall objective of this NRSA Individual Fellowship is to develop skills that will allow the candidate to become a physician-scientist and pursue an academic research career focused on translational investigation of airways disease. The applicant and his mentors have devised a training approach that includes both research and didactic instruction. This approach will establish the knowledge and intellectual framework essential for a successful research career. The proposal concerns chronic obstructive pulmonary disease (COPD). COPD is the fourth leading cause of death in the United States. Despite the profound morbidity and mortality, the specific immunologic mechanisms are yet to be fully elucidated. Recent data suggest the macrophage is at the forefront as it plays a critical role in host defense and eventually tissue repair. Many studies have characterized macrophages from human COPD patients compared to healthy subjects identifying different levels of surface markers and cytokine expression suggesting distinct macrophage function in COPD patients. In particularly, macrophages from COPD patients compared to healthy controls exhibit reduced expression of surface markers important for immunity (adhesion molecules, antigen presentation molecules and recognition markers), as well as alterations in cytokine production. Although impaired macrophage cytokine release has been associated with increased exacerbations and worse severity of COPD, the specific macrophage surface markers and cytokines associated with increased COPD morbidity remains unknown. Our preliminary analysis demonstrates reduced airway macrophage CD80 expression and increased TGF-?1 is associated with worse respiratory symptoms and worse lung function, respectively. It is not known if this association holds true for other measures of COPD morbidity and exacerbation frequency. Additionally, the regulation of airway macrophage CD80 expression remains poorly understood. Our intriguing preliminary data indicates a reverse correlation between TGF-?1 production and CD80 expression.
In Specific Aim 1, the candidate will examine the association of (a) airway macrophage CD80 expression and (b) TGF-?1 production with COPD morbidity (lung function, exacerbation risk and respiratory symptoms). Multicolor flow cytometry will be used to determine macrophage surface marker expression and intracellular cytokine production. We hypothesize that both reduced CD80 expression and increased TGF-?1 production are independently associated with worse COPD morbidity.
Specific Aim 2 will define the TGF- ?1/CD80 axis of the airway macrophage. Exposure to TGF-?1 and TGF-?1 blocking antibodies ex vivo will elucidate if this biologic pathway can be modulated. These experiments will explore the immunologic mechanisms leading to worse morbidity in COPD patients with the ultimate hope of personalizing therapy for those with low CD80 expression and potentially identifying new therapeutic targets.
Abnormal inflammation and immunologic function are responsible for the pathogenesis of chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the United States. The exact pathophysiology remain unknown, however recent data suggest the macrophage is fundamental to disease development as it plays a critical role in host defense and eventually tissue repair. We are interested in the specific airway macrophage dysfunction that is associated with worse COPD morbidity in human subjects. Our project proposes elucidating if the TGF-?1/CD80 biologic pathway is associated with worse morbidity and modulating the macrophage ex vivo with exposure to TGF-?1 and TGF-?1 blocking antibodies. If we can better elucidate the specific biologic pathway associated with worse COPD morbidity, therapy can be tailored to those with reduced CD80 and inhibition of the pathway can be explored as a potential therapeutic target in patients with COPD .