Asthma is an allergic airway inflammation-driven disease. Eosinophils have emerged as a key contributor to allergic airway inflammation. Recent studies have found that neutrophils can aggravate allergic airway inflammation, leading to the development of severe asthma. It is now known that eosinophil infiltration into the lungs is mediated by T helper 2 (Th2) cells, whereas neutrophil infiltration into the lungs is mediated by Th17 cells. While asthma can be effectively treated with glucocorticoids, long-term use of glucocorticoids yields excessive toxicity. In addition, severe asthma patients don?t respond optimally to current therapy. Thus, a better understanding of asthma pathobiology is warranted for developing novel treatment strategies. In a preliminary study, our laboratory has identified a critical role of RhoA GTPase in integrating glucose metabolism and Th2 and Th17 cell differentiation. Importantly, we have found that RhoA couples glycolysis to Th2 cell-mediated allergic airway inflammation. These findings lead to our overall hypothesis that RhoA-mediated glycolysis pathways in Th2 and Th17 cells regulate the development of allergic airway inflammation, and targeting these pathways will lead to novel intervention of asthma.
In Aim 1, we will determine the molecular mechanism by which RhoA regulates Th2/Th17 cell differentiation and allergic airway inflammation development. We will test if RhoA regulates Th2 differentiation through a miR-19a-mTORC2-glycolysis signaling hub, but Th17 differentiation through a miR-19b-mTORC1-glycolysis signaling node. We will further investigate whether the two glycolysis pathways are important for the development of allergic airway inflammation mediated by mixed Th2/Th17 cells.
In Aim 2, we will dissect the role of RhoA immediate downstream effectors in RhoA-mediated glycolysis, Th2/Th17 cell differentiation and allergic airway inflammation.
In Aim 3, we will demonstrate a proof of concept for pharmacologically targeting RhoA-regulated glycolysis pathways in asthma. We expect that this research will not only advance our understanding of allergic airway inflammation pathobiology, but may also provide new biological targets for asthma prevention and therapy.
The Principal Investigator has recently identified a critical role of an enzyme called RhoA in integrating glucose metabolism, immune Th2 and Th17 cell differentiation and Th2 cell-mediated asthma development. The proposed work will determine how RhoA regulates glucose metabolism in Th2 and Th17 cells and whether RhoA-regulated glucose metabolism pathways in Th2 and Th17 cells contribute to the development of and can be targeted to treat asthma. Successful execution of the project will not only advance our understanding of asthma pathobiology, but may also provide new biological targets for asthma therapy.
