Defining the role of primary cilia in development and disease. (360G-Wellcome-082311_Z_07_Z)

The primary cilium is enjoying renewed interest having been ascribed sensory roles and more recently associated with regulation of aspects of development. We discovered the debilitating Bardet-Biedl syndrome (BBS) arises from ciliary dysfunction. Our recent data implicate BBS proteins in cell polarisation (PCP) and sonic hedgehog (Hh) transduction potentially linking the processes via their role in intraflagellar transport (IFT). We aim to identify the precise point of action of BBS proteins in relation to PCP and Hh signalling. We stand to gain insights into fundamental biological processes and understand why they produce certain phenotypes when disrupted. BBS is one of an emerging new group of disorders, the ciliopathies. Through comparisons with BBS, we predicted other ciliopathies such as the often lethal, Jeune syndrome (JS). By specifically searching out ciliary genes we identified the first JS gene (IFT80), the protein for which is directly involved in IFT. We aim to investigat e function of Ift80 by generating a conditional mouse knockout and studying different aspects of organ involvement. Finally, we will extend our preliminary observations of rapamycin rescue of renal cysts in bbs and ift80 morphant zebrafish to Bbs mutant mice (which also develop kidney cysts) paving the way for human trials.