Primary Faculty/Secondary Faculty

Paul Moore, M.D.

Associate Professor of Pediatrics

2200 Children's Way, Nashville, TN, 9500

Research Description

My work is focused on understanding the molecular basis of genetic variations in asthma. Over the past decade, a number of candidate genes have been linked to asthma. Despite these linkage studies, the mechanistic basis of how genetic variation results in an asthma phenotype is not well understood.

For our in vitro studies, we utilize cultured human airway smooth muscle (HASM) cells, isolated from the trachealis muscle of lung transplant donors since airway smooth muscle is the primary target of bronchodilators used to treat asthma. My primary focus been on variation in the Beta-2-adrenergic receptor (ADRB2) gene. We have demonstrated that polymorphisms in the regulatory and coding regions of ADRB2 influence desensitization in HASM, and we are trying to demonstrate the mechanisms by which polymorphisms result in functional changes. Our approach includes a combination of pharmacokinetic and molecular techniques, including promoter bashing, receptor binding, and measurements of relevant signaling pathways.

With better understanding of the ADRB2 gene, we hope to establish a paradigm by which genetic variability in other G protein coupled receptors alters airway smooth muscle responses. We have demonstrated that genetic variability in the IL-4 receptor alters responses in the Th2 signaling pathway, including TARC expression and eotaxin release. Furthermore, we have shown that responses to corticosteroids in HASM vary by ADRB2 genotype and by IL-4R genotype in the absence of variability in known glucocorticoid-response-elements, suggesting a novel signaling pathway by which corticosteroids influence HASM responses.

The results of our in vitro observations have direct clinical application. I am directly involved in establishing a cohort of children with severe asthma admitted to the Pediatric Intensive Care Unit for an asthma exacerbation. Our project is focused on identifying genetic factors that influence ethnic disparities in severe pediatric asthma. In the Center for Human Genetics, we are using the latest analytical tools to understand the influence of gene-gene and gene-enviroment interactions that lead to severe asthma.A number of follow up studies are being generated based on our preliminary questions. We plan to look at follow up of those patients in the Pediatric Continuity Clinic, and also bring a group back to the GCRC to understand whether physiologic differences persist beyond the acute exacerbation. In addition, we are looking at a cohort of adults hospitalized with an asthma exacerbation.

Selected Publications