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Targeting Glutamine (Q) Metabolism in the Renal Ciliopathies

Objective

Polycystic Kidney Disease (PKD) is one of the most common monogenic disorders and a major genetic cause of kidney failure. The disease is characterised by progressive formation of fluid-filled cysts originating from renal tubular epithelial cells, ultimately leading to loss of kidney function and the need for dialysis or transplantation. Both autosomal dominant and recessive forms belong to the renal ciliopathies, a group of genetic disorders caused by dysfunction of the primary cilium, a cellular organelle essential for environmental sensing and signalling.
Our laboratory has uncovered a previously unrecognised role of primary cilia in metabolic regulation. We discovered that primary cilia sense extracellular glutamine and regulate mitochondrial metabolism, revealing a new metabolic signalling axis linking ciliary function to cellular energy homeostasis. Within this pathway, we identified asparagine synthetase (ASNS) as a key mediator required for glutamine-dependent signalling and metabolic adaptation in cystic epithelial cells.
Building on these discoveries, the ERC Advanced Grant QtCilia has demonstrated that metabolic reprogramming is a central feature of PKD and represents a tractable therapeutic vulnerability. In particular, PKD cells rely on increased glutamine utilization mediated by ASNS. Inhibition of ASNS has shown strong therapeutic potential in preclinical models, supporting the development of ASNS-targeting therapies.
The QrCiliopathies Proof-of-Concept project will translate this discovery into a therapeutic innovation by developing first-in-class small-molecule inhibitors targeting ASNS. The project will optimize lead compounds identified through high-throughput screening and evaluate their therapeutic potential through a structured validation pipeline combining cellular disease models and in vivo PKD models.

Fields of science (EuroSciVoc)

Programme(s)

Topic(s)

Funding Scheme

HORIZON-ERC-POC - HORIZON ERC Proof of Concept Grants

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Call for proposal

(opens in new window) ERC-2026-POC

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Host institution

OSPEDALE SAN RAFFAELE SRL
Net EU contribution
€ 150 000,00
Address
VIA OLGETTINA 60
20132 Milano
Italy
Region
Nord-Ovest Lombardia Milano
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
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Total cost
No data

Beneficiaries (1)