Cilia-associated Human Diseases.

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The primary cilium is a solitary cell-surface projection found on nearly all cells in our bodies that functions as a major signaling center. Signaling pathways that play critical roles in development and cancer, including Hh, Wnt, and PDGF, have been linked to cilia. Nearly 50 human genetic diseases, called “ciliopathies,” are caused by mutations in gene products required for cilia structure or function. Ciliopathies include some of the most common human genetic diseases, such as polycystic kidney disease. Patients suffering from these syndromes display pleiotropic phenotypes, including polycystic organs, sensory defects, brain malformations, craniofacial abnormalities, skeletal defects, and obesity. Its important to note that these are very common pathological phenotypes in sporadic human maladies as well, suggesting that cilia-based mechanisms will be relevant well beyond inherited human diseases.

The >500 proteins that populate the cilia “parts list” represent a completely unexplored therapeutic landscape, both for ciliopathies and for cancer-relevant signaling pathways such as Hh and Wnt. To effectively develop cilia-targeted drugs, we must understand the molecular circuitry (the protein interactions and enzymatic reactions) that link signal transduction to primary cilia.

We use Hedgehog signaling as a facile model to reveal general principles of cilia-centered signal transduction. In fact, many ciliopathies show defects in Hedgehog signaling and we are interesting
in unraveling the detailed biochemical pathophysiology underlying these “Hedgehogopathies.”