? CORE C The Animal and Imaging Core will support Projects of the Program by providing logistic and scientific oversight, and performance of complex longitudinal animal experiments. Various murine asthma models representing different human asthma endotypes across the TH2-TH17 immune spectrum, including ovalbumin allergen, house dust mite, Aspergillus, high fat diet, and a combination of high fat diet plus house dust mite will be made available to projects to test the therapeutic effects of IL-17A pathway inhibition using peptidomimetics and sGC stimulators/activators on airway hyper-reactivity and inflammation. Pharmacokinetics studies of compounds will be performed to determine optimal route, dose and frequency of administration. Intranasal, oral gavage, intravenous and intraperitoneal injection, and nebulized administration are available. Measurements of airway hyper-reactivity, 4Dx airflow, tracheal densitometry, airway inflammation and airway remodeling will be performed to analyze drug effects. 4Dx Imaging is a cutting edge X-ray tomographic velocimetric quantification of regional airflow allowing us to identify specific part(s) of the lungs targeted by the new compounds. A cloud- based mouse laboratory information management system (mLIMS) will be used to record all experimental procedures and to securely store all mouse data. All required instruments and expertise are found in the Core or made available through collaboration, such as equipment for 4Dx imaging and pharmaceutical industry guidance for drug formulation for the various routes of administration. The Core expedites results and reduces cost of Projects through the use of shared model systems and, most importantly, assists in the generation of preclinical data to move new, more effective, therapeutics into the clinic. New model systems of endotypes of asthma, preclinical studies and airflow imaging increase overall translational innovation of the Program.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL103453-10
Application #
9986005
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Noel, Patricia
Project Start
Project End
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Herjan, Tomasz; Hong, Lingzi; Bubenik, Jodi et al. (2018) IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling. Nat Immunol 19:354-365
Sweeny, Elizabeth A; Singh, Anuradha Bharara; Chakravarti, Ritu et al. (2018) Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells. J Biol Chem 293:14557-14568
Reichard, Andrew; Wanner, Nicholas; Stuehr, Eric et al. (2018) Quantification of airway fibrosis in asthma by flow cytometry. Cytometry A 93:952-958
Asosingh, Kewal; Weiss, Kelly; Queisser, Kimberly et al. (2018) Endothelial cells in the innate response to allergens and initiation of atopic asthma. J Clin Invest 128:3116-3128
Reichard, Andrew; Asosingh, Kewal (2018) The role of mitochondria in angiogenesis. Mol Biol Rep :
Yang, Hui; Zhu, Yun; Chen, Xing et al. (2018) Structure of a prokaryotic SEFIR domain reveals two novel SEFIR-SEFIR interaction modes. J Struct Biol 203:81-89
Cai, Gang; Zhu, Liang; Chen, Xing et al. (2018) TRAF4 binds to the juxtamembrane region of EGFR directly and promotes kinase activation. Proc Natl Acad Sci U S A 115:11531-11536
Zein, Joe G; Love, Thomas E; Erzurum, Serpil C (2017) Asthma Is Associated with a Lower Risk of Sepsis and Sepsis-related Mortality. Am J Respir Crit Care Med 196:787-790
Zepp, Jarod A; Zhao, Junjie; Liu, Caini et al. (2017) IL-17A-Induced PLET1 Expression Contributes to Tissue Repair and Colon Tumorigenesis. J Immunol 199:3849-3857
Stober, Vandy P; Johnson, Collin G; Majors, Alana et al. (2017) TNF-stimulated gene 6 promotes formation of hyaluronan-inter-?-inhibitor heavy chain complexes necessary for ozone-induced airway hyperresponsiveness. J Biol Chem 292:20845-20858

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