Functional analysis of novel, small-molecule modulators of BMP and Wnt signaling in zebrafish.

The primary objective of this project is to characterize novel small-molecule modulators of the BMP and Wnt signaling pathways. Both pathways play critical and diverse roles during embryogenesis and in the progression of a broad host of diseases. In particular, BMP and Wnt signaling is essential for proper skeletal development and joint morphogenesis as well as for the regulation of postnatal joint physiology and joint tissue remodeling. Zebrafish - an ideal model organism for chemical genetics and for in vivo studies of BMP and Wnt signaling - will be used as the primary biological system for initial pathway elucidation and in vivo functionation of these compounds. Subsequently, structural analogs of select compounds will be tested and prioritized for improved pathway specificity, potency and reduced toxicity, using both in vitro assays (mammalian cells) and in vivo assays (zebrafish, chick limb outgrowth model). Finally, select compounds with optimal efficacy/toxicity profiles will be tested in mouse models of osteoarthritis. The long-term goal of this project is the development of druk-like lead compounds for the treatment of osteoarthritis - an increasingly important disorder because of aging populations in most industrialized nations, and one for which there are currently few effective treatment options.

Keywords:Zebrafish, BMP, Wnt, Osteoarthritis

Disciplines:Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences, Orthopaedics