Descrizione del progetto
Far progredire la diagnosi e il trattamento delle ciliopatie pediatriche
Molte cellule presentano sulla loro superficie ciglia primarie, antenne basate su microtubuli, fondamentali per controllare processi di segnalazione essenziali durante lo sviluppo e il mantenimento dei tessuti. Le ciglia disfunzionali possono portare a ciliopatie, rare malattie genetiche con sintomi diversi. Le morbilità comuni associate alle ciliopatie comprendono la malattia renale cronica e la malattia renale in fase terminale, che richiede dialisi e trapianto. Il progetto TheRaCil, finanziato dall’UE, sfruttando database europei di pazienti, bioraccolte, solidi modelli preclinici e strumenti basati sull’intelligenza artificiale, intende migliorare la diagnosi, la prognosi e le opzioni di trattamento delle ciliopatie renali pediatriche. La ricerca comprende la riconversione di molecole terapeutiche e l’uso di oligonucleotidi antisenso per colpire direttamente le varianti geniche del rene. Inoltre, i ricercatori identificheranno i geni e i biomarcatori che modificano la malattia e perfezioneranno la stratificazione dei pazienti per migliorare i criteri di idoneità al trattamento.
Obiettivo
Ciliopathies are a large group of rare and severe genetic diseases caused by dysfunction of the primary cilium, a microtubule-based cell surface antenna that controls key signaling output required during development and tissue homeostasis. Cilium dysfunction leads to complex disorders with high genetic heterogeneity and overlapping phenotypes. Despite the broad clinical spectrum, chronic kidney disease (CKD) leading to end stage kidney disease (ESKD) is a common cause of morbidity across ciliopathies. Currently, the only available standard of care for CKD is based on dialysis and transplantation. Renal ciliopathies represent a main cause of ESKD during childhood and despite the identification of more than 40 causative genes, it remains difficult to predict the severity of the disease as well as the risk of appearance (if not present at diagnosis) and the rate of progression of renal failure. TheRaCil therefore aims: (1) to improve diagnosis and prognosis of at risk pediatric renal ciliopathy patients, and (2) to implement therapeutic approaches aimed at targeting shared pathological pathways, at modifying mRNA targets of the causative or modifier genes by antisense oligonucleotides and by the repurposing of available molecules. These goals will be achieved through the federation of our unique databases of pediatric renal ciliopathies cases available across Europe, which will allow a better stratification of patients, the identification of modifier genes and markers of disease progression. Bioinformatics approaches will be used to integrate patients’ biological and genetic data as well as multi-omics and functional analyses from patients samples and preclinical models. These analyses should lead to the identification of shared targetable pathological pathways as well as of patients eligible for the identified new therapeutic approaches which will be evaluated in robust preclinical models.
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Invito a presentare proposte
HORIZON-HLTH-2022-DISEASE-06-two-stage
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HORIZON-RIA - HORIZON Research and Innovation ActionsCoordinatore
75015 Paris
Francia