Descrizione del progetto
Un fegato su chip che segue i modelli di sonno-veglia nativi per prevedere il metabolismo dei farmaci
Il fegato è il sito principale per il metabolismo dei farmaci, convertendoli in composti idrosolubili che possono essere escreti nei fluidi corporei. I processi di ricerca e sviluppo dei farmaci devono prevedere vari parametri legati al metabolismo e alla tossicità degli stessi. Tuttavia, i modelli animali o i saggi esistenti non riescono a riprodurre l’ambiente dinamico del fegato. Per superare questo problema, il progetto CircaCHIP, finanziato dall’UE, ha sviluppato un dispositivo liver-on-a-chip (fegato su chip) basato sulla microfluidica, che cattura le dinamiche metaboliche e le oscillazioni di temperatura e ormoni del tessuto nativo. Questa piattaforma innovativa fornisce il primo dispositivo che riprende i ritmi circadiani ed è in grado di prevedere con precisione il metabolismo, la clearance e la tossicità dei farmaci.
Obiettivo
The liver is responsible for the systemic regulation of human metabolism, responding to a dynamically changing hormonal and nutritional environment. These physiological dynamics limited our ability to model human metabolism in our efforts to create efficient pharmaceutical interventions for prevalent metabolic diseases, such as fatty liver disease, obesity, and type-2 diabetes. In addition, physiological dynamics impact the pharmacokinetics and toxicity of drugs due to circadian changes in drug metabolism, affecting our ability to formulate efficient pharmaceutical interventions or properly assess drug toxicity (i.e. Chronopharmacology). The problem stems from our inability to model the dynamics of human metabolism in vitro, and compounded by the failure of animal models to predict human response due to differences in physiology, metabolic regulation, and an inverted day/night cycles. In addition, in vitro hepatocytes show little to no metabolic function and lack the physiological complexity of human tissue. Therefore, there is a pressing need to develop models that mimic human physiological complexity. Recently, we established groundbreaking libraries of expandable human hepatocytes (Levy et al. Nature Biotechnology 2015) and a cutting-edge liver-on-chip platform that tracks metabolic dynamics in real time (Bavli et al. PNAS 2016). Our technology explained the idiopathic toxicity of acetaminophen and the idiosyncratic toxicity of troglitazone and was recently highlighted by the H2020 program. Here, we describe the development of a novel platform that captures the synchronization of circadian rhythms in self-assembled human micro-livers by microfluidic oscillations of temperature and hormones. Our next generation model for liver metabolism will present a quantum leap in capability, offering to go beyond animal models by predicting time-of-day dependent toxicity and drug clearance. In addition, we will enable the rational design of a new generation of pharmaceuticals
Campo scientifico
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugs
- medical and health sciencesclinical medicineendocrinologydiabetes
- medical and health sciencesbasic medicinepharmacology and pharmacypharmacokinetics
- engineering and technologyother engineering and technologiesmicrotechnologyorgan on a chip
- medical and health scienceshealth sciencesnutritionobesity
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-POC - Proof of Concept GrantIstituzione ospitante
91904 Jerusalem
Israele