Our laboratory has a long-standing interest in the study of cilia associated disorders with a special emphasis on those displaying renal cystic disease. Clinical variability is often observed in genetic diseases and one of the leading themes in the next 10 years of medical genetics research will be to understand the molecular bases of this variability to improve the management, genetic counseling and possibly treatment of these patients. OFD type I is a rare inherited form of renal cystic disease and mutations in HNF-1β are associated with a variety of renal phenotypes. Patients belonging to both groups display a high degree of clinical variability. We have selected few mutations representative of the different phenotypes observed in the two groups of patients. We are currently characterizing these mutations by applying OMICS approaches to identify a) transcripts differentially expressed between wild-type and mutated forms of the proteins or b) proteins interacting only with the mutated or the wild-type proteins or vice versa. The results obtained will undergo bioinformatic analysis and the results will be used to formulate experimental hypotheses that will then be validated in the available animal models and patient's samples.
A different line of research, in collaboration with Alessia Indrieri, is focused on mitochondrial diseases (LHON and Leigh syndrome (LS). Biochemical and genetic heterogeneity of LS has so far prevented the development of effective treatments. Gene/mutation-independent strategies would thus represent the ideal approach for LS. We proposed that a synergic and fine-tuned modulation of pathways acting on mitochondria may ensure a more effective neuroprotective effect in mitochondrial disorders. We demonstrated that miR-181a and miR-181b (miR-181a/b) regulate key genes involved in mitochondrial biogenesis and function. NDUFS4 encodes an MRC subunit whose mutations are responsible for one of the most severe forms of LS. Mice with Ndufs4inactivation develop a severe encephalopathy resembling LS and resulting in death before post-natal day 60. We tested the effect of miR-181a/b modulation in Ndufs4 animals. Our results show that inactivation of miR181a/b in Ndufs4KO mice results in a) increased survival rate as shown by Kaplan-Meier analysis, b) improved locomotor activity analyzed by behavioral studies and c) increased Oxygen Consumption Rate highlighted by biochemical analysis. We propose that miR-181a/b may represent novel gene-independent therapeutic targets not only for LS but also for a wide-range of neurodegenerative disorders caused by mitochondrial dysfunction.
Malattie genetiche rare dovute a disfunzione ciliare e mitocondriale studiate al TIGEM
Da anni il nostro laboratorio studia rare malattie genetiche associate a disfunzione di un piccolo organello cellulare, il ciglio primario, una specie di antenna con la quale la cellula "sente" l'ambiente cellulare per poi trasmettere segnali necessari per il funzionamento cellulare. Tra le diverse malattie associate a questa condizione ci occupiamo di quelle caratterizzate da rene policistico cercando di capire perché' gli individui con variazioni di sequenza in geni importanti per la funzione di questo organello mostrano aspetti clinici tanto diversi. Speriamo in questo modo di avere informazioni che possano indirizzare le scelte terapeutiche. Inoltre, in collaborazione con altri gruppi del TIGEM stiamo studiando l'effetto terapeutico della modulazione di un piccolo RNA sulle malattie con disfunzione mitocondriale ed in particolare nella Leber Hereditary optic neuropathy (malattia di LHON) e nella malattia di Leigh.