in the Cell Biology and Physiology Department at UNC-Chapel Hill
Currently there are no known direct chemical modulators of IF proteins, which is hindering functional understanding of this important cytoskeletal system. Our major goal is to identify small molecule compounds that can disassemble the intermediate filament network in a rapid and selective manner. Using a combination of biochemical and cell-based screens we are identifying IF-targeting small molecule compounds. We are currently investigating the pharmacological properties of, and performing structure-activity studies on several promising lead compounds and their analogs.
DISCOVERY OF CHEMICAL PROBES TO STUDY INTERMEDIATE FILAMENT FUNCTION
POST-TRANSLATIONAL MODIFICATIONS REGULATING INTERMEDIATE FILAMENT PROTEOSTASIS
There are more than 80 human diseases associated with intermediate filament gene mutations (www.interfil.org). Most IF diseases are rare and orphan. We are investigating shared mechanisms among these rare diseases to ultimately enable faster and less expensive development of therapeutics for IF diseases. In collaboration with Dr. Raluca Dumitru and the UNC Stem Cell Core, we are developing clinically relevant systems for IF disease modeling and drug screening utilizing novel cellular reprogramming methods on patient cells.
IF proteins are extensively regulated by post-translational modifications (PTMs), resulting in altered protein solubility, filament assembly, and protein interactions. Abnormal PTM profiles distinguish normal from disease-mutant IF proteins. We are identifying novel PTMs and testing the effects of PTM-targeting drugs on IFs and disease-associated IF mutants (such as Alexander Disease-associated GFAP mutants). We seek an understanding of which PTMs act as global “master switches” that control the balance between filaments and aggregates. Ultimately we want to use this information to uncover the functional significance of IF protein aggregation.
DEVELOPMENT OF NOVEL CELLULAR MODELS OF INTERMEDIATE FILAMENT DISEASES