This proposal seeks to renew a successful UCSF Asthma and Allergic Diseases Cooperative Research Center dedicated to identifying molecular phenotypes (endotypes) of asthma and understanding how these endotypes contribute to disease pathophysiology. The proposal builds on our track record of using cell and molecular biology tools, animal models, and human studies focused on the airway epithelium to dissect asthma mechanisms, relate mechanisms to disease phenotypes, predict responses to existing therapies, and identify new therapeutic targets. Work from our Center demonstrated the central importance of direct effects of the type 2 cytokine IL-13 on airway epithelial cells, identified the type 2 asthma endotype as the dominant feature in a large asthma subgroup, established the ability of asthma endotyping to predict therapeutic responses, and showed how IL-13-induced changes in secretory cells cause mucus plugging in fatal asthma. Recent studies from our group and other laboratories implicate other pathways, notably the interferon (IFN) and ER stress pathways, in some individuals with asthma. Despite the considerable progress made by our Center and many others, there is still an urgent need for a more complete understanding of asthma disease mechanisms and more effective therapies for the many individuals with type 2-high or type 2-low asthma who do not respond well to current treatments. This proposal includes two projects that are highly interrelated and share a focus on the epithelium as both a key participant in asthma pathogenesis and a useful sensor for asthma endotyping. Project 1 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 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 will recruit and carefully characterize participants with asthma and healthy controls and provide biospecimens that will be used extensively in both projects. An Administrative Core will coordinate Center activities. Through the proposed studies we expect to gain new insights into the mechanistic bases of asthma endotypes and better understand how to target novel pathways important in specific endotypes.

Public Health Relevance

PROGRAM NARRATIVE Our Center is focused on understanding how the epithelial cells that line the airways are involved in causing different forms of asthma. Our studies will uncover new knowledge about mechanisms of asthma and help to pave the way for new treatments for this common disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI077439-12
Application #
9636421
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Davidson, Wendy F
Project Start
2008-04-01
Project End
2023-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
12
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Bhakta, Nirav R; Christenson, Stephanie A; Nerella, Srilaxmi et al. (2018) IFN-stimulated Gene Expression, Type 2 Inflammation, and Endoplasmic Reticulum Stress in Asthma. Am J Respir Crit Care Med 197:313-324
Levin, Albert M; Gui, Hongsheng; Hernandez-Pacheco, Natalia et al. (2018) Integrative approach identifies corticosteroid response variant in diverse populations with asthma. J Allergy Clin Immunol :
Wong-McGrath, Kelly; Denlinger, Loren C; Bleecker, Eugene R et al. (2018) Internet-Based Monitoring in the Severe Asthma Research Program Identifies a Subgroup of Patients With Labile Asthma Control. Chest 153:378-386
Oh, Sam S; Du, Randal; Zeiger, Andrew M et al. (2017) Breastfeeding associated with higher lung function in African American youths with asthma. J Asthma 54:856-865
Sherenian, M G; Cho, S H; Levin, A et al. (2017) PAI-1 gain-of-function genotype, factors increasing PAI-1 levels, and airway obstruction: The GALA II Cohort. Clin Exp Allergy 47:1150-1158
Bonser, Luke R; Erle, David J (2017) Airway Mucus and Asthma: The Role of MUC5AC and MUC5B. J Clin Med 6:
Yi, L; Cheng, D; Zhang, K et al. (2017) Intelectin contributes to allergen-induced IL-25, IL-33, and TSLP expression and type 2 response in asthma and atopic dermatitis. Mucosal Immunol 10:1491-1503
Sundaram, Aparna; Chen, Chun; Khalifeh-Soltani, Amin et al. (2017) Targeting integrin ?5?1 ameliorates severe airway hyperresponsiveness in experimental asthma. J Clin Invest 127:365-374
Thakur, Neeta; Barcelo, Nicolas E; Borrell, Luisa N et al. (2017) Perceived Discrimination Associated With Asthma and Related Outcomes in Minority Youth: The GALA II and SAGE II Studies. Chest 151:804-812
Wells, Karen E; Cajigal, Sonia; Peterson, Edward L et al. (2016) Assessing differences in inhaled corticosteroid response by self-reported race-ethnicity and genetic ancestry among asthmatic subjects. J Allergy Clin Immunol 137:1364-1369.e2

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