EUCILIA

"Pathophysiology of rare diseases due to ciliary dysfunction: nephronophthisis, Oral-facial-digital type 1 and Bardet-Biedl syndromes"

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 Obiettivo del progetto (Objective)

'Primary cilia have been recognized on nearly all-mammalian cells. Emerging data suggest that they act as cellular antennae with diverse motility and sensory functions, detecting a wide variety of signals. As such, defects in cilia formation or function have profound effects on the development of body pattern and the physiology of multiple organ systems. Ciliary defects underlie a wide range of human disorders, including the rare and heritable Bardet-Biedl (BBS), Oro-facial-digital type 1 (OFD1) and nephronophthisis (NPHP) syndromes. Each of these disorders present with defining features but all are characterized by polycystic renal disease. The proteins encoded by the genes responsible for these disorders, as well as those implicated in heritable forms of cystic kidneys, are all located to the cilium/basal body/centrosome complex, suggesting that ciliary dysfunction might be the unifying pathogenic concept underlying cystic kidney disease. However, the molecular mechanisms remain undetermined. We propose to use BBS, OFD1 and NPHP syndromes as model systems to study the physiological role of primary cilia, with special emphasis on their role in the genitourinary tract and in the development of renal cysts. The experimental plan proposes to generate and make available to the scientific community in vitro and in vivo models to study the physiological role of primary cilia and of OFD1, BBS and NPHP proteins in the formation and function of the primary cilium. These tools will allow the analysis of the ciliary protein interaction network and of the downstream pathway in the absence of BBS, OFD1, or NPHP. Finally, we propose to identify and evaluate potential therapeutic agents. The biological relevance and significance of the results obtained will have implications far beyond the rare OFD1, BBS and NPHP patients and may shed light on the mechanisms underlying the role of primary cilia in polycystic kidney disease paving the way to possible new therapeutic approaches.'

Introduzione (Teaser)

European research is delving into the role of cilia, minute hair-like projections on cell surfaces. As cilia exert profound effects on body development, their malfunction could play an important part in the pathology of many diseases.

Descrizione progetto (Article)

Recent research has uncovered important roles for cilia. Acting like cell antennae, they can detect a wide variety of signals. As such, defects in their function can have wide-ranging effects on the physiology of many organs.

The EU-funded EUCILIA project used animal models (Xenopus, zebrafish and mouse) as well as cell culture systems to unravel the role of cilia in cell function. The team of scientists focused on rare diseases including Bardet-Biedl (BBS) and nephronophthisis (NPHP) syndromes. Interestingly, these disorders are both characterised by polycystic kidney disease (PKD) and the researchers put special emphasis on the role of cilia in renal cyst development, a key symptom of PKD.

Consortium scientists made a list of phenotypic changes found in the disease models. Moreover, they identified proteins involved in signalling pathways in these rare genetic disorders. The dynamics of protein trafficking and recruitment in relation to cilia were also elucidated to determine the effect of the mutations involved in diseases like BBS and NPHP.

What is more, the fact that the cilia are present in all cell types suggests abnormalities in these structures could have a role in recent epidemics such as type I diabetes, hypertension and obesity.

EUCILIA work has shed light on the role of proteins involved in Wnt signalling linked to tubulogenesis relevant to the validation of new therapeutic approaches.

Results of the EUCILIA project including the mutant models of mice, zebrafish and Xenopus will be made available to the research community at large to expand on the substantial knowledge platform that the researchers generated. Further information can be found on the project website.