The broad goal of this project is the pharmacological validation of GIV, a nonreceptor guanine nucleotide exchange factor (GEF), for liver fibrosis. GIV sits at the hub of profibrogenic signaling in liver fibrosis, and is required for the key physiological events that lead to this condition: the migration, proliferation and extracellular matrix deposition of hepatic stellate cells (HSC). GIV is an ideal drug target as it is strongly ov erexpressed in the disease state, and functions independently of the extracellular signaling receptors used to instigate fibrosis.
The aims of the proposal are to develop a biochemical primary screening assay, and a multiparametric phenotypic secondary assay in HSCs. The primary assay is based on the steady state GDP levels associated with GEF and its cognate G protein G?i3. The GEF activity assay will be used to screen an orthogonally pooled compound library. Hits will be confirmed and shown to be GEF specific. Following hit expansion, functional activity will be verified using the phenotypic assays. In phase II, these compounds will be profiled for selectivity and tested in animal models.
This proposal will help to find new drugs for liver fibrosis, a potentially deadly condition that can develop into cirrhosis and/or liver cancer. It is prevalent in patients with alcoholism, and is more likely to affects patients who are obese or have met abolic syndrome. Exciting new laboratory findings indicate a new approach is warranted, and this proposal seeks to realize the potential to better understand and potentially treat this disease.
