Projektbeschreibung
Dem natürlichen Schlaf-Wach-Rhythmus folgende Leber-on-a-Chip prognostiziert Arzneimittelstoffwechsel
Die Leber ist der wichtigste Ort, an dem Arzneimittel verstoffwechselt werden. Sie wandelt sie in wasserlösliche, über Körperflüssigkeiten ausscheidbare Verbindungen um. In den verschiedenen Phasen der Arzneimittelforschung und -entwicklung müssen etliche Parameter im Zusammenhang mit dem Wirkstoffmetabolismus und der Toxizität vorhergesagt werden. Tiermodelle oder die bereits existierenden Tests können jedoch die dynamische Umgebung der Leber nicht gut nachbilden. Zur Lösung dieses Problems hat das EU-finanzierte Projekt CircaCHIP ein auf Mikrofluidik beruhendes Leber-on-a-Chip-Bauelement entwickelt, das die Stoffwechseldynamik sowie Temperatur- und Hormonschwankungen des nativen Gewebes erfasst. Diese neuartige Plattform stellte die erste Vorrichtung dar, welche zirkadiane Rhythmen berücksichtigt und den Stoffwechsel, die Ausscheidung und die Toxizität von Arzneimitteln genau vorhersagen kann.
Ziel
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
Wissenschaftliches Gebiet
- 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
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-POC - Proof of Concept GrantGastgebende Einrichtung
91904 Jerusalem
Israel