The chronic inflammation in asthma is due largely to the persistence of Th2 lymphocytes and Th2 cytokines/chemokines produced by both the structural cells of the lung as well as the infiltrating CD4+ lymphocytes, eosinophils, and basophils and the resident mast cells, leading to progressive loss of lung function. Recent studies have shown that IL-25 functions as an important mediator of Th2 responses and lies upstream of the classical Th2 cytokine responses. We recently discovered that Act1, a novel E3 ubiquitin Iigase, is an essential signaling molecule for IL-25 signal transduction and is recruited to the IL-25R upon ligand stimulation. Interestingly, Act1 deficiency in epithelial cells effectively attenuates IL-25-mediated allergic pulmonary inflammation, and Act1 deficiency in T cells also results in significantly diminished Th2 responses and lung inflammation. Based on these findings, we hypothesize that the IL-25 induced Act1 mediated signaling pathway is essential for Th2 cell responses and allergic pulmonary inflammation through distinct effects on epithelial and T cell compartments. To test this, we propose two Specific Aims. First, we investigate the mechanistic role of IL-25-induced Act1-mediated signaling pathway in Th2 responses and allergic pulmonary inflammation. Second, we determine the molecular mechanism by which Act1 mediates IL-25 signaling. In accord with the translational goals of our TPPG, we use the Information obtained in this project to develop decoy (inhibitory) peptides to disrupt the Acti-IL-25 receptor interaction. Decoy inhibitory peptides in the IL-25 signal transduction pathway are explored as a new therapeutic strategy for allergic pulmonary inflammation. Project 2 benefits significantly from interactions with other projects in the TPPG, and relies heavily on TPPG Cores for resources such as human and murine airway organotypic cultures. Altogether, the TPPG fosters the translation of Project 2 bench research studies to development of novel patient therapeutics.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-A)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
United States
Zip Code
Navaneethan, Udayakumar; Parsi, Mansour A; Lourdusamy, Vennisvasanth et al. (2015) Volatile organic compounds in bile for early diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis: a pilot study. Gastrointest Endosc 81:943-9.e1
Cowan, Douglas C; Taylor, D Robin; Peterson, Laura E et al. (2015) Biomarker-based asthma phenotypes of corticosteroid response. J Allergy Clin Immunol 135:877-83.e1
Tang, W H Wilson; Wang, Zeneng; Shrestha, Kevin et al. (2015) Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure. J Card Fail 21:91-6
Alkhouri, N; Eng, K; Cikach, F et al. (2015) Breathprints of childhood obesity: changes in volatile organic compounds in obese children compared with lean controls. Pediatr Obes 10:23-9
Lauer, Mark E; Aytekin, Metin; Comhair, Suzy A et al. (2014) Modification of hyaluronan by heavy chains of inter-?-inhibitor in idiopathic pulmonary arterial hypertension. J Biol Chem 289:6791-8
Ratanamaneechat, Suphagaphan; Neumann, Donald R; Difilippo, Frank P et al. (2014) Redox imaging of inflammation in asthma. Am J Respir Crit Care Med 189:743-6
Kennedy, David J; Fan, Yiying; Wu, Yuping et al. (2014) Plasma ceruloplasmin, a regulator of nitric oxide activity, and incident cardiovascular risk in patients with CKD. Clin J Am Soc Nephrol 9:462-7
Tang, W H Wilson; Topol, Eric J; Fan, Yiying et al. (2014) Prognostic value of estimated functional capacity incremental to cardiac biomarkers in stable cardiac patients. J Am Heart Assoc 3:e000960
Navaneethan, Sankar D; Wehbe, Edgard; Heresi, Gustavo A et al. (2014) Presence and outcomes of kidney disease in patients with pulmonary hypertension. Clin J Am Soc Nephrol 9:855-63
Xu, Weiling; Janocha, Allison J; Leahy, Rachel A et al. (2014) A novel method for pulmonary research: assessment of bioenergetic function at the air-liquid interface. Redox Biol 2:513-9

Showing the most recent 10 out of 25 publications