Metabolic Reprogramming in Arrhythmogenic Right Ventricular Cardiomyopathy: a Human Ips-Based Multisystem Approach

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is inherited cardiac disease characterized by the replacement of cardiomyocytes (CMs) by fibrofatty tissue. Causative mutations have been identified in around 60% of patients, mainly in genes encoding for proteins associated with mechanical cell junctions. As far there is no effective and evidence-based medical therapy in preventing progression of the disease. If we clarify the components of metabolites in ARVC CMs and identify the dysfunctional pathways and expressions of genes related to lipid metabolism, we may find potentially effective therapy in preventing the progression of the disease. In this project, We hypothesize the underlying mechanisms of intracellular lipid accumulation in ARVC CMs include two: (1) inappropriate fatty acid synthesis from glucose and acetate and (2) impaired fatty acid utilization as energy source in mitochondria. To test our hypothesis, we plan to establish human induced pluripotent stem cell (hiPS)-derived cardiomyocytes (CMs) from ARVC patients and establish metabolomic (liquid chromatography-time-of-flight-mass spectrometry), transcriptional profiles and perform mitochondria function analysis. Finally, to evaluate if the mutation in ARVC causatively contribute to the metabolic dysfunction, we will perform gene editing in ARVC hiPS using a CRISPER approach and re-evaluate the lipid and transcriptomic profiles of corrected ARVC-hiPS-CMs. We hope through the project, we can tell a complete story of cellular processes and pathologies in ARVC, highlighting on metabolic profiles and mitochondria function. The study would provide the capability to examine the intact and functional cellular system, enabling comprehensive investigations into metabolic pathways and phenotypes, which may help find a novel therapeutic strategy to stop or slow the disease progression.

Project IDs

Project ID:PC10901-0300
External Project ID:MOST107-2314-B182-073-MY3
StatusFinished
Effective start/end date01/08/2031/07/21

Keywords

  • induced pluripotent stem cell
  • arrhythmogenic right ventricular cardiomyopathy
  • metabolomics
  • liquid chromatography-time-of-flight-mass spectrometry

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