Grant: CIHR Fellowship

Fibrosis, or chronic organ scarring, is a major medical problem Canada-wide and worldwide: 45% of deaths in the Western world are associated with this condition. Fibrosis is prevalent because it is a healing attempt that occurs in common diseases including hypertension, diabetes, and chronic inflammation. I propose to study how a fibrosis-promoting, "pro-fibrotic", transcription factor regulates turnover of an antenna-like structure called the primary cilium. This work expands our knowledge of fibrosis to a new frontier (the cilia field), and may inform new therapies that will broadly improve Canadian health and beyond. The primary cilium is a sensory, antenna-like structure, present in many organs of the human body. Hundreds of genes and proteins build a cilium. Mutations in many cilia genes cause serious diseases called "ciliopathies". Though ciliopathies often feature fibrosis, the control of cilium assembly during fibrosis remained a mystery until recently when the Kapus Lab made a key discovery in this area. We found that a pro-fibrotic transcription factor (MRTF) affects cilia. Transcription factors, by definition, regulate gene expression which occurs in completely different part of the cell than the primary cilium. This result reveals a surprising new function for MRTF. My research project will determine how MRTF regulates the primary cilium, first by using state-of-the-art microscopy to visualize MRTF within the primary cilium, and then by testing how MRTF works with canonical cilia proteins during cilium assembly. A main motivation in pursuing this project, is the opportunity to answer a long-standing question in biology: How does a healthy cell "decide" to adopt a new fate in disease? By delving into a surprising link between MRTF and cilia, my project builds towards a larger picture of disease dynamics in which transcription factors directly tune the cell's antenna to respond to environmental signals. This result is paradigm shifting in our field.