Principal Investigator/Program Director (Last, first, middle): Harper, Richart RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? l Yes m No 1.a. If YES to Human Subjects Is the IRB review Pending? l Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 4 5 6 Human Subject Assurance Number 00004557 2. * Are Vertebrate Animals Used? m Yes l No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? m Yes m No IACUC Approval Date: Animal Welfare Assurance Number 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract 4788-Abstract.pdf Mime Type: application/pdf 7. * Project Narrative 8083-Project_Narrative.pdf Mime Type: application/pdf 8. Bibliography &References Cited 9810-LITERATURE_CITED.pdf Mime Type: application/pdf 9. Facilities &Other Resources 6021-facilities_&_resources.pdf Mime Type: application/pdf 10. Equipment 7572-equipment.pdf Mime Type: application/pdf Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Harper, Richart Abstract Rhinovirus (RV) is an important pathogen present in the respiratory tract epithelium of a significant proportion of asthma patients during severe pulmonary exacerbations. Mechanisms by which the human respiratory tract epithelium identifies acute RV infection, mechanisms used immediately by the human respiratory tract epithelium to respond to this infection, and how these mechanisms are impaired in asthmatics have not been fully elucidated. Our recent studies of DUOX2 suggest this protein is critical for normal antiviral host defense. We hypothesize that DUOX2 is a central component for host defense against RV infection in respiratory tract epithelium: When activated by RV, DUOX2 produces hydrogen peroxide (H2O2), hypohalous acid, or reactive nitrogen species to (a) directly inactivate rhinovirus and (b) stimulate the expression of early antiviral genes, but (c) antiviral activity is suppressed in the presence of Th2 cytokines such as interleukin-4 (IL- 4) or interleukin-13 (IL-13).
Specific Aims : Test the predictions that (1) DUOX2-mediated generation of H2O2, hypohalous acids, or reactive nitrogen species directly inactivates RV, (2) DUOX2- mediated generation of H2O2 results in the early activation of antiviral genes, and (3) IL-4 blocks DUOX2-mediated antiviral activity by inhibiting transcriptionally-mediated DUOX2 expression. We will use human respiratory tract epithelial cells for all the studies outlined for this project. Relevance to Public Health: We anticipate these studies will reveal novel mechanisms by which the respiratory tract epithelium activates innate host defense against RV infection. These studies will potentially elucidate specific mechanisms that are impaired in asthmatic patients. These foundational studies will allow us to investigate specific mechanisms responsible for RV-induced asthma exacerbations in the future. Project Description Page 6

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL085311-02S1
Application #
7837499
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Noel, Patricia
Project Start
2009-07-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2011-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$263,763
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Chang, Sandra; Linderholm, Angela; Harper, Richart (2015) DUOX-Mediated Signaling Is Not Required for LPS-Induced Neutrophilic Response in the Airways. PLoS One 10:e0131810
Harper, Richart W; Zeki, Amir A (2015) Immunobiology of the critical asthma syndrome. Clin Rev Allergy Immunol 48:54-65
Schivo, Michael; Aksenov, Alexander A; Linderholm, Angela L et al. (2014) Volatile emanations from in vitro airway cells infected with human rhinovirus. J Breath Res 8:037110
Price, David; Harper, Richart; Henderson, Mark C (2013) Progressive cervical myelopathy as presentation of sarcoidosis. J Gen Intern Med 28:855-6
Chang, Sandra; Linderholm, Angela; Franzi, Lisa et al. (2013) Dual oxidase regulates neutrophil recruitment in allergic airways. Free Radic Biol Med 65:38-46
Xu, Changhong; Linderholm, Angela; Grasberger, Helmut et al. (2012) Dual oxidase 2 bidirectional promoter polymorphisms confer differential immune responses in airway epithelia. Am J Respir Cell Mol Biol 47:484-90
Linderholm, Angela Lee; Onitsuka, June; Xu, Changhong et al. (2010) All-trans retinoic acid mediates DUOX2 expression and function in respiratory tract epithelium. Am J Physiol Lung Cell Mol Physiol 299:L215-21
Hill 3rd, Thomas; Xu, Changhong; Harper, Richart W (2010) IFNgamma mediates DUOX2 expression via a STAT-independent signaling pathway. Biochem Biophys Res Commun 395:270-4