Albano Carlo Meli, Ph.D.

Project: CARDIOSTEM - Reprogramming of human skin fibroblasts into functional cardiomyocytes - insights into molecular pathology of genetic cardiac diseases

Person in Charge: prof. Ing. Petr Dvořák, CSc.

Host institution: Faculty of Medicine

Country of Origin: France 

Country of scientific activity: USA

Project duration: 24 months

Scientific panel: Life sciences

Abstract:

Hypertrophic cardiomyopathy (HCM) is a leading cause of mortality in developed countries. The majority of HCM-related gene mutations affect the heart cell’s contractile unit, the sarcomere, causing the heart to become enlarged and dysfunctional. While much is known about primary causes of HCM, little is understood about the signaling events initiated by the mutant sarcomere. Studies using animal models have established potential signaling pathways that may contribute towards cardiac pathology. Proteins that regulate sarcoplasmic reticulum (SR) calcium release and re-uptake, such as ryanodine receptor/calcium release channel (cardiac RyR2), SR calcium-ATPase, phospholamban or sodium/calcium exchanger, are being modified in HCM. This suggests that calcium-related pathological mechanisms precede the impaired cardiac contractility and may serve as potential targets of pharmacological intervention. Due to lack of a suitable model, molecular pathology of abnormal calcium handling in HCM has never been investigated in human cardiomyocytes.
Reprogramming of skin fibroblasts from patients that harbor cardiovascular disease-related mutations currently sparks special interest for getting insight into the underlying mechanisms of human cardiovascular diseases. In this project, patient skin biopsies will be used to derive HCM-specific human induced pluripotent stem cells (HCM-hiPSCs) and to develop human cardiovascular disease model. We hypothesize that cardiomyocytes derived from HCM-hiPSCs represent an excellent model for investigation of molecular mechanisms of intracellular calcium handling. We hypothesize that stabilization of the cardiac RyR2 by calcium channel stabilizers may prevent the hypertrophic response. In this way, we assume that drugs that can prevent these molecular calcium-related events might be good candidates for treating manifestation of the disease in individuals with sarcomere protein gene mutations.