Asthma is one of the most common chronic diseases in the world. Synergistic and mechanistic research by our group has contributed substantially to define fundamental pathogenic processes underlying asthma inflammation and remodeling, including: (1) excessive response of adaptive immunity, most often via CD4* T helper lymphocyte (TH2) cells;(2) lack of resolution of inflammation related to abnormal extracellular matrix that amplifies influx and activation of inflammatory cells;and (3) generation of excessive reactive oxygen and nitrogen species that promotes remodeling. Based upon our cumulative findings, the unifying hypothesis of our Program is that asthma results from prolonged and excessive, predominantly TH2, inflammation with failed attempts at resolution and repair leading to airway remodeling. To test this, our Program organizes a comprehensive approach through 4 projects designed to study inter-related roles of extracellular and cellular-molecular components, including: the newly discovered IL-25 (TH2 cytokine) pathway that relies on ubiquitin iigase Act1 to mediate allergic airway inflammation via independent (and non-redundant) effects on airway epithelium and T cells (project 2);the amplification and persistence of airway epithelial response to TH2 cytokines due to inactivation of tyrosine phosphatase in the pathologic oxidative state of asthma (project 1);increased and aberrant deposition of pathological hyaluronan-rich extracellular matrix that impedes resolution of inflammation (project 3);and the recently uncovered eosinophil peroxidase-catalyzed protein modification of carbamylation that is linked to tobacco-smoke exposure, and independent of adaptive immunity induces an asthma-like phenotype. Our multi-disciplinary rigorous scientific approaches reveal mechanisms, and offer the greatest opportunities for successful translation to patient benefits. Three scientific Cores (Clinical, Biorepository, Animal Model) and an Administrative Core strengthen each project and expedite translation by providing expert service and easy access to well-defined clinical samples and primary cells in organotypic culture, and murine asthma models. Collectively, translational research is integrated throughout the Program, builds upon the fundamental discoveries made by our NIH-funded investigators, capitalizes extensively on support from the Cleveland Clinic Translational Science Award (CTSA), and benefits from FDA approval in place for human allergen challenge models. Altogether, the scope and scale of the science, the efficient and productive investigators, and the consistent translational focus promises fundamental scientific discoveries that will impact patient care over the years of the Program.

Public Health Relevance

Asthma is a chronic inflammation of the airway that arises from genetic and environmental factors. The chronic non-resolving inflammation leads to progressive airway structural changes over time. The Asthma Inflammation Research Translational Program proposes to study the pathogenic mechanisms of the chronic inflammation and translate the discoveries to improve the care of asthmatic patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL103453-01
Application #
7941370
Study Section
Special Emphasis Panel (ZHL1-CSR-A (M1))
Program Officer
Noel, Patricia
Project Start
2011-08-02
Project End
2016-06-30
Budget Start
2011-08-02
Budget End
2012-06-30
Support Year
1
Fiscal Year
2011
Total Cost
$2,673,763
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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