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Microfabrication-Based Rational Design of Transcriptional-Metabolic Intervention for the Treatment of Hepatitis C Virus (HCV) Infection

Objective

Hepatitis C Virus (HCV) infection affects over 3% of the world population and is the leading cause of chronic liver disease worldwide. Current treatments are effective in only 50% of the cases and associated with significant side effects. Therefore, there is a pressing need for the development of alternative treatments. Recently, our group and others demonstrated that the HCV lifecycle is critically dependent on host lipid metabolism. In this context, we demonstrated that the grapefruit flavonoid naringenin blocks HCV production through PPAR± and LXR±, transcriptional regulators of hepatic lipid metabolism. While these results are promising, our ability to rationally control metabolic pathways in infected cells is limited due to an incomplete understanding of the regulation of hepatic metabolism by its underlying transcriptional network. This project aims to develop a comprehensive model of hepatic metabolism by integrating metabolic fluxes with transcriptional regulation enabling the rational design of transcriptional-interventions which will minimize HCV replication and release. Our approach is to develop two microfabricated platforms that will enable high-throughput data acquisition and a human-relevant screening. One component is the Transcriptional Activity Array (TAA), a microdevice for the high-throughput temporal acquisition of transcriptional activity data. The second is the Portal Circulation Platform (PCP) which integrates intestinal absorption module with a liver metabolism compartment enabling the high-throughput human-relevant screening of treatments as a substitute to animal experiments. This work will lead to the development of novel drug combinations for the treatment of HCV infection and impact the treatment of diabetes, obesity, and dyslipidemia.

Field of science

  • /natural sciences/biological sciences/microbiology/virology
  • /medical and health sciences/health sciences/infectious disease/RNA virus
  • /natural sciences/biological sciences/biochemistry/biomolecules/lipids

Call for proposal

ERC-2009-StG
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

THE HEBREW UNIVERSITY OF JERUSALEM
Address
Edmond J Safra Campus Givat Ram
91904 Jerusalem
Israel
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 994 395
Principal investigator
Yaakov Nahmias (Dr.)
Administrative Contact
Hani Ben-Yehuda (Ms.)

Beneficiaries (1)

THE HEBREW UNIVERSITY OF JERUSALEM
Israel
EU contribution
€ 1 994 395
Address
Edmond J Safra Campus Givat Ram
91904 Jerusalem
Activity type
Higher or Secondary Education Establishments
Principal investigator
Yaakov Nahmias (Dr.)
Administrative Contact
Hani Ben-Yehuda (Ms.)