Obese asthmatics have higher disease burden and worse pulmonary function, but are poorly responsive to current asthma medications, as compared to normal-weight children with asthma. This high disease burden with no effective medications highlights an urgent need for development of novel therapies for obesity-related asthma. Development of novel therapies is directly linked to elucidation of the pathobiology of obesity-related asthma. We and others have found evidence of systemic non-atopic TH cell inflammation in obese asthmatic children that correlates with pulmonary function deficits specific to obesity-related asthma. Using an RNA-Seq- based unbiased probe into the immunobiology of the non-atopic TH cell responses, we identified upregulation of several genes (DOCK5, VAV2, CDC42EP4, PAK3, MLK3, and PLD1) in the CDC42 pathway in obese asthmatic TH cells relative to normal-weight asthmatic TH cells. CDC42EP4 and DOCK5 gene expression correlated with lower airway obstruction only in obese asthmatic children. Based on the key role that CDC42 plays in T cell migration, adhesion, activation, and differentiation of nave TH cells into TH1 and TH17 subsets, our results support a novel role for the CDC42 pathway in non-atopic immune responses in obesity-related asthma. Since TH cell adhesion to the airway smooth muscle (ASM) causes ASM activation, in light of our pilot findings of greater cytosolic calcium release in obese ASM in response to carbachol, a muscarinic agent, compared to normal-weight ASM, we hypothesize that CDC42 mediated increased migration and adhesion of obese asthmatic TH cells to ASM causes activation of muscarinic pathways in the ASM; this CDC42 mediated crosstalk between TH cells and ASM underlies the association of systemic non- atopic immune response with pulmonary function deficits in obesity-related asthma. We will utilize well- characterized ASM cells from obese and normal-weight individuals from Dr. Panettieri's lab and TH cells from extensively phenotyped obese and normal-weight urban minority asthmatic children collected during my K23 award to study the following aims.
In Aim 1, we will test the hypothesis that CDC42 activation increases migration and adhesion of obese asthmatic TH cells to ASM cells.
In Aim 2, we will determine if the obese asthmatic TH cell adhesion to ASM is a trigger event for ASM activation leading to activation of muscarinic pathways. Evidence of crosstalk between CDC42-mediated TH cell responses and ASM activation is of utmost clinical relevance since it links systemic non-atopic immune responses with airway physiology in obese asthma. This evidence will support future investigation of CDC42 pathway to identify proteins downstream of CDC42 that underlie non-atopic inflammation that impacts pulmonary function. We also expect to identify pathways in ASM as therapeutic targets for obesity-related asthma, a disease entity for which there are currently no effective treatments.
Obesity-related asthma is associated with high disease burden with no effective therapy, because its mechanisms are not well understood. This research proposal will investigate the mechanisms by which obese asthmatic T cells interact with the airway smooth muscle and thereby define links between non-allergic inflammation and pulmonary function deficits in obesity-related asthma. These studies will provide the foundation for investigation of novel therapeutic targets for obesity-related asthma.
