The National Institute of Allergy and Infectious Diseases will provide $7 million to support a third five-year cycle for UCSF's Asthma and Allergic Diseases Cooperative Research Center (AADCRC). The UCSF AADCRC was founded by Dean Sheppard, who is now turning over the Program Director role to David Erle. The new five year cycle, entitled "Understanding Asthma Endotypes," has two projects and one scientific core. Porject 1, led by Erle, will determine mechanisms and consequences of heightened epithelial sensitivity to IL-13, examine the basis of IL-13-induced changes in physical properties of mucus that cause airway obstruction, and dissect the contributions of epithelial ER stress in both type 2- and IFN-high asthma. Project 2, led by Prescott Woodruff, will determine the clinical significance of interferon-driven inflammation and airway epithelial ER stress in asthma, establish whether interferon-driven inflammation and airway epithelial ER stress are resistant to and predict poor response to existing asthma therapies, and determine whether specific inhibition of airway epithelial ER stress with a novel therapeutic, KIRA8, improves AHR, inflammation and mucus production in allergic asthma models. A Clinical Subject and Biospecimen Core, led by Nirav Bhakta, will recruit and carefully characterize participants with asthma and healthy controls and provide biospecimens that will be used extensively in both projects.