Yohannes Ghebre Lab


About the Lab


Regulation of the nitric oxide synthase (NOS) pathway using small molecules is a major strategy we employ to translate our basic research insights into useful therapy. Recently, we applied high throughput screening (HTS) technology to discover small molecules that directly regulate this pathway. Intriguingly, we discovered that proton pump inhibitors (PPIs; a class of FDA-approved drug developed to treat gastric acidity) directly inhibit the NOS pathway and regulate many of the downstream processes associated with overly active iNOS including tissue inflammation and fibrosis.

More recently, we demonstrated that PPIs suppress lung inflammation and fibrosis in an experimental model of chemotherapy-induced acute lung injury, in part by regulating the transcription of inducible NOS (iNOS) and several classic pro-inflammatory cytokines. In subsequent studies, we demonstrated that PPI possess pleiotropic salutary effect through regulation of cell proliferation, oxidative and nitrosative stress, inflammation and fibrosis. Our retrospective study of interstitial lung disease (ILD) database of lung fibrosis (idiopathic pulmonary fibrosis; IPF) patients also revealed that PPIs significantly extended transplant-free survival of the patients (3.4 years versus 1.9 years). Emerging metanalysis databases also suggest that PPIs possess antitumor activity including chemosensitization, and extend the overall survival of patents with breast cancer as well as head-and-neck squamous carcinoma (HNSCC).

Currently, we are working towards reformulating and repurposing generic drugs for new indications including inflammatory and fibrotic conditions that result from chemoradiation therapy including pneumonitis, dermatitis, mucositis; common and dose-limiting complications in the treatment of cancer.

In addition to the pharmacology projects, we are working to solve co-crystal structure of enzymes bound to small molecules of interest. One of such projects is currently underway to solve the structure of a PPI bound to one of the enzymes in the NOS pathway. We are collaborating with several groups to pursue our research interests.