Asthma is a chronic inflammatory disease in which the genetic background and the immune system interact with environmental factors to elicit overt manifestations of the disease. As a consequence of the chronic inflammation, lung morphology may become altered even in milder forms of the disease. Extracellular matrix (ECM) components such as hyaluronan (HA) and proteoglycans are deposited in the submucosa, and it is thought that the accumulation of these molecules compromises the biomechanical properties of the airway tissue. In the lung, ECM has traditionally been considered to be Inert scaffolding, having only a mechanical role in supporting and maintaining tissue structure. However, recent findings indicate that the role of ECM molecules is much broader than previously thought. These molecules play a role in cell-cell interactions, cellmatrix interactions, cell proliferation, cell locomotion and inflammation. Investigators are also increasingly aware that hyaluronan exhibits a variety of molecular size-dependent biologic functions. Specifically, the large polymers and very small oligomers are anti-inflammatory and anti-angiogenic, while intermediate-sized hyaluronan fragments take on pro-inflammatory and pro-anglogenic properties. Our preliminary studies support a role for HA In the pathogenesis of asthma and In inflammatory cell recruitment. Our studies also suggest a role for HA not only as a biomarker for disease activity but also as a potential therapeutic agent to modulate ainA/ay Inflammation. Thus, we hypothesize that HA is a central mediator in the organization of inflammation and remodeling in the asthmatic airway and that HA will be a biomarker for disease activity, and low molecular weight (MW) HA will inhibit inflammation and be a useful therapeutic agent in the treatment of asthma. To test this hypothesis we propose the following specific alms.
Aim 1 Investigates the utility of HA as a biomarker of inflammation In the asthmatic ainway and determine correlation with disease activity, or severity.
Aim 2 investigates the utility of HA as a therapeutic in the asthmatic ainway.
Aim 3 Investigates the mechanisms of HA production by the airway smooth muscle cells (SMCs) and determines the functional consequences of lymphocytes binding to the HA. Together with Projects 1, 2, and 4, Project 3 plans mechanistic aims that have clear translational potential to clinical asthma care. The synergistic research and expert TPPG cores provide substantial benefit to Project 3 and assure success of the overall goals to translate fundamental discoveries into improvements for asthma patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL103453-04
Application #
8686055
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
Ghosh, Arnab; Stuehr, Dennis J (2017) Regulation of sGC via hsp90, Cellular Heme, sGC Agonists, and NO: New Pathways and Clinical Perspectives. Antioxid Redox Signal 26:182-190
Israel, Laura; Wang, Ying; Bulek, Katarzyna et al. (2017) Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity. Cell 168:789-800.e10
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
Modena, Brian D; Bleecker, Eugene R; Busse, William W et al. (2017) Gene Expression Correlated with Severe Asthma Characteristics Reveals Heterogeneous Mechanisms of Severe Disease. Am J Respir Crit Care Med 195:1449-1463
Chen, Jiwang; Sysol, Justin R; Singla, Sunit et al. (2017) Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and Is a Therapeutic Target in Pulmonary Arterial Hypertension. Circulation 135:1532-1546
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
Gu, Xiaodong; Huang, Ying; Levison, Bruce S et al. (2016) Identification of Critical Paraoxonase 1 Residues Involved in High Density Lipoprotein Interaction. J Biol Chem 291:1890-904
Martin, Bradley N; Wang, Chenhui; Zhang, Cun-jin et al. (2016) T cell-intrinsic ASC critically promotes T(H)17-mediated experimental autoimmune encephalomyelitis. Nat Immunol 17:583-92
Reeves, Stephen R; Kaber, Gernot; Sheih, Alyssa et al. (2016) Subepithelial Accumulation of Versican in a Cockroach Antigen-Induced Murine Model of Allergic Asthma. J Histochem Cytochem 64:364-80
Cheong, Hoi I; Asosingh, Kewal; Stephens, Olivia R et al. (2016) Hypoxia sensing through ?-adrenergic receptors. JCI Insight 1:e90240

Showing the most recent 10 out of 121 publications