Ciliopathies are pleiotropic diseases with a wide spectrum of human phenotypes. These include cyst formation in the liver and pancreas, respiratory disorders and a predisposition to diabetes and cancer. The pleiotropic nature of these disorders may reflect the many roles cilia play in physiology and signalling, highlighting the clinical importance of understanding their function in organ development and homeostasis. Despite the biological importance of cilia and decades of research, many aspects of cilia assembly and disassembly remain elusive. The earliest steps of cilia assembly involve conversion of the centrosome into a basal body, which anchors the cilia to the plasma membrane. Odf2 is one of the only proteins known to be important for this process, thus Ofd2 mutant cells lack cilia. During cell cycle re-entry primary cilia disassemble, the basal body dislodges from the plasma membrane and duplicates to serve as the mitotic centrosome. We recently identified Pitchfork, which functions in basal body-to-centrosome conversion and regulates embryonic patterning. The overall aim of this proposal is to better understand the cellular and bio-molecular mechanisms underlying ciliary disease. We will conditionally delete Odf2 and Pitchfork during embryogenesis and organogenesis. This will reveal the different requirements for the process of cilia assembly and disassembly in embryonic development, organ formation and homeostasis. The phenotypes will be analyzed at all levels of complexity. Subcellular imaging and identification of protein interaction partners will uncover the molecular basis of cilia assembly and disassembly. In summary, this project will decipher mechanisms underlying a wide spectrum of human ciliary disease and will open new avenues of clinical research.
Field of science
- /medical and health sciences/basic medicine/physiology/homeostasis
- /natural sciences/biological sciences/biochemistry/biomolecules/proteins
Call for proposal
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