This is an application for a K23 award for Nirav Bhakta, MD, PhD, a postdoctoral fellow in pulmonary medicine at the University of California, San Francisco. Dr. Bhakta is beginning a career as a young investigator in translational research in asthma. Asthma is a chronic inflammatory disease of the airways in the lungs that leads to recurrent episodes of wheezing, cough and shortness of breath. There has been a dramatic increase in the prevalence, morbidity, and economic burden associated with asthma over the past 40 years. This K23 award will provide Dr. Bhakta with the support necessary to accomplish the following goals: (1) to develop an independent patient-centered translational research career focused on airway diseases; (2) to advance the application of multi-color flow cytometry to human tissue samples to quantitatively evaluate inflammatory pathways; (3) develop expertise in using airway epithelial cells in culture as a model system to interpret human data; and (4) to apply advanced biostatistical methods to the development of biomarkers to predict response to molecularly-targeted therapies. To achieve these goals, Dr. Bhakta has assembled a mentoring team comprised of a primary mentor, Dr. Prescott Woodruff, an expert in translational asthma research and molecular phenotyping of asthma; a co-mentor, Dr. John Fahy, an expert in translational asthma research and airway epithelial cell biology; and 4 grant advisory committee members: Dr. Mark Ansel, an immunologist with expertise in immune cell subsets and multi-color flow-cytometry; Dr. Dean Sheppard, a senior researcher studying inflammatory pathways in mouse models of asthma; and Dr. David Erle, an expert in the application of high-throughput technologies and statistical methods to study gene networks in asthma; and Dr. Mark Segal, a senior biostatistician with extensive experience in high-throughput data analysis. There is growing recognition that asthma is not a single disease, but rather has many different forms leading to variability in severity and response to medications between patients. It is likely that these differences are driven by the predominance of distinct underlying pathways of inflammation, the discovery of which would inform the development of novel targeted therapies. Identification of one such pathway, inflammation driven by T helper 2 (Th2) cells, has led to a novel blood biomarker (periostin) which predicts response to Th2-targeted therapy, proving the concept that molecular phenotyping can guide cytokine-targeted therapies. However, Th2 inflammation explains only a subset of asthma, and there is a need to identify other pathways, especially for the 10% of asthmatics who are severe and do not respond to standard therapies. The proposed research will investigate the role of one such pathway, inflammation driven by IL-17 cytokines, which preliminary findings lead us to hypothesize is associated with heightened eosinophilic inflammation and two cardinal features of severe asthma: excessive airway narrowing and mucous overproduction. An ongoing bronchoscopy study in severe asthmatics will be leveraged to obtain airway washings and tissues to test these hypotheses. The numbers of IL-17 cytokine- expressing cells will be assessed in these tissues with flow cytometry and microscopic examination, and their association with inflammatory cells, clinical airway narrowing, and mucous overproduction determined. Importantly, the proposed study will combine this data with experiments on isolated cells to develop biomarkers in the blood and sputum that reflect IL-17-driven inflammation in the lung. These biomarkers have the potential to improve asthma care by providing a test to identify the individuals most likely to respond to IL-17-targeted drugs already in development by pharmaceutical companies.

Public Health Relevance

Asthma is a very common lung disease affecting 7% of adults in America . The 5-10% of asthmatics that have severe disease account for much of the public health burden of the disease, and have unmet therapeutic needs because of a sub-optimal response to currently available treatments. The goals of this work are to characterize types of inflammation in severe asthma to guide the development of new therapies and tests to predict response to these treatments.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1)
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Tigno, Xenia
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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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
Durack, Juliana; Lynch, Susan V; Nariya, Snehal et al. (2017) Features of the bronchial bacterial microbiome associated with atopy, asthma, and responsiveness to inhaled corticosteroid treatment. J Allergy Clin Immunol 140:63-75
Phipatanakul, Wanda; Mauger, David T; Sorkness, Ronald L et al. (2017) Effects of Age and Disease Severity on Systemic Corticosteroid Responses in Asthma. Am J Respir Crit Care Med 195:1439-1448
Duvall, Melody G; Barnig, Cindy; Cernadas, Manuela et al. (2017) Natural killer cell-mediated inflammation resolution is disabled in severe asthma. Sci Immunol 2:
Denlinger, Loren C; Phillips, Brenda R; Ramratnam, Sima et al. (2017) Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations. Am J Respir Crit Care Med 195:302-313
Hoffman, Sidra M; Chapman, David G; Lahue, Karolyn G et al. (2016) Protein disulfide isomerase-endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness. J Allergy Clin Immunol 137:822-32.e7
Lawson, Devon A; Bhakta, Nirav R; Kessenbrock, Kai et al. (2015) Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature 526:131-5
Bhakta, Nirav R; Erle, David J (2014) IL-17 and ""TH2-high"" asthma: Adding fuel to the fire? J Allergy Clin Immunol 134:1187-8