Descripción del proyecto
Un «hígado en un chip» que sigue los patrones de sueño y vigilia nativos y predice el metabolismo de los fármacos
El hígado es el principal centro para el metabolismo de los fármacos, donde se convierten en compuestos hidrosolubles que pueden excretarse mediante los fluidos corporales. Los procesos de investigación y desarrollo de fármacos deben predecir diversos parámetros relacionados con la toxicidad y el metabolismo de los medicamentos. Sin embargo, los modelos animales o los ensayos existentes no logran captar el entorno dinámico del hígado. El proyecto CircaCHIP, financiado con fondos europeos, se ha propuesto abordar esta cuestión y ha desarrollado un dispositivo de «hígado en un chip» basado en la microfluídica que capta la dinámica metabólica y las oscilaciones de temperatura y hormonas de los tejidos nativos. Esta nueva plataforma constituye el primer dispositivo que sintetiza los ritmos circadianos y que puede predecir de forma precisa el metabolismo, la eliminación y la toxicidad de los medicamentos.
Objetivo
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
Ámbito científico
- 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
Programa(s)
Régimen de financiación
ERC-POC - Proof of Concept GrantInstitución de acogida
91904 Jerusalem
Israel