Grant: Project Grant

Cilia function a bit like a satellite antenna, protruding from most cells and relaying information from the surroundings back to the cell. An increasing number of conditions are being identified where cilia function abnormally, and these disorders (termed ciliopathies), represent important causes of pediatric and adult-onset disease. Unfortunately, such conditions are largely untreatable at present. In experiments undertaken in cell lines, as well as in two animal models, we have discovered that one member (FOXC1) of a larger transcription factor family has roles in controlling the structure and function of cilia. Altering the dose of Foxc1 induces significant changes to the length of the primary cilium, and perturbs the function of key pathways that utilize the cilium for signal transduction. This has intriguing implications due to the diverse diseases caused by mutation of this gene, which include glaucoma (an ocular disorder), hydrocephalus (a condition in which the flow of cerebrospinal fluid through the brain is perturbed), and stroke. This grant proposes to investigate the precise mechanisms involved. Specific aims study the mechanistic basis of hydrocephalus, examine the Hedgehog signaling pathway which depends on the primary cilium for function, and investigate the contribution of vesicular shedding to this area of cell biology. The overarching goal is to define the underlying mechanisms so as to facilitate future development of novel therapeutic approaches.