Cilia are hair-like specialised structures that protrude from the surface of most non-proliferative eukaryotic cells. Motile cilia propel fluid, for example to remove mucous and dirt from lung epithelial cells. Alternatively, immotile or primary cilia serve as antennas for receiving and transducing signals, for example by the sensory cilia of retinal photoreceptors.
The EU-funded
SYSCILIA (A systems biology approach to dissect cilia function and its disruption in human genetic disease) project has investigated the function of ciliary proteins in health and disease. For this purpose, they developed models capable of predicting the outcome of ciliary protein perturbations.
Research work revealed the impact of cilia involvement on a range of organs. Cilia are an integral part of nephron development via a highly conserved programme in the kidney to extend tubules.
SYSCILIA researchers also found that blocking one-up regulated pathways triggered other pathways. This phenomenon is sometimes observed in cancer treatment and has to be taken into account in ciliotherapy design.
Knockout and knockdown techniques unearthed many genes required for ciliary formation and function that were subsequently analysed. Mechanisms of action of ciliary disease genes were investigated including links of ciliopathy proteins with response to DNA damage, chromatin remodelling and proteasomes.
Using whole genome small interfering RNA-based reverse genetics screening has presented many genes involved in newly discovered pathways in human ciliary disease. Allele analysis for pathogenicity was performed for almost 800 ciliary genes.
A cross-species analysis revealed details of ciliary machinery evolution. With another consortium, a new ciliary 'Gene Ontology' has been developed with 50 new terms.
For drug design, treated patient cells were subject to both known and newly developed drugs for modulation of cilia. As some ciliopathies can be caused by nonsense mutations, the team tested the effectiveness of translational read-through inducing drugs. For up to 20 % of patients harbouring nonsense mutations, modified aminoglycosides and PTC124 were found to hold great potential.
Results of the SYSCILIA study have formed a firm knowledge platform for understanding basic biological processes underlying the role of cilia in human disease. Dissemination of the project success underscore this potential – a total of 171 publications since the project started in mid-2010.