The molecular role of telomerase in cardiomyocyte function, proliferation and cardiac regeneration

• Applicant: Professor Christian Bär, Ph.D.
• Subject Area: Cardiology, Angiology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 341572583

Significant advances in modern medicine have led to a steady increase in life expectancy of our society. Consequently the incidence of age-related diseases such as cancer and cardiovascular disease strongly increased. Given that around 80% of heart failure patients are currently older than 65 years of age, a further dramatic increase in cardiovascular diseases is expected. Ageing is a complex and multifaceted process. One of the hallmarks of molecular ageing is the progressive shortening of telomeres with increasing age because telomerase (TERT), the enzyme that maintains telomeres, is silenced after birth. In this regard, our previous studies demonstrated that therapeutic re-activation of TERT through gene therapy in a mouse model of myocardial infarction has beneficial effects on cardiac function and subsequently survival. The aim of this project is to decipher basis for this cardioprotection of TERT on the molecular level and to test whether TERT -based strategies may be exploited to enhance cardiac regeneration.Strikingly, new born mice can fully regenerate their heart after an insult such as myocardial infarction which is conferred by actively proliferating cardiomyocytes (CM). This capacity is lost within the first week of life and coincides with the silencing of cardiac TERT expression. To study this correlation and the impact of TERT on cardiac regeneration we will employ the neonatal mouse model of myocardial infarction and combine it with modulated TERT expression. For the latter we will test the cardiac regeneration potential after infarction in mice without TERT (knock-out) and with constitutively active TERT expression (through gene therapy) in comparison to their respective wild-types. By analyzing the molecular differences in these conditions we aim at identifying molecular switches which are directly linked with CM proliferation and cardiac regeneration.In addition, we will test TERT in vitro in human cells. To this end, we will use induced pluripotent stem cell (hiPSC) derived CMs. This system will allow us to study the role of TERT during hiPSC to CM differentiation through targeted manipulation of the TERT gene as well as by the use of patient-derived iPSCs with mutations in the TERT gene. Moreover, this system enables us to produce an unlimited number of CMs for subsequent functional testing and gene expression analyses. Finally, we will test our hypothesis that TERT re-activation in human CMs may be of therapeutic use. To do so, we will test these modified CMs in preclinical, 3-dimensional ex vivo model, so called Engineered Heart Tissue.Taken together, the main goal of our studies in mouse and human cellular systems is to decipher the functional interplay between TERT and cardiac regeneration. By doing so it is our vision to contribute to the development of new therapeutic strategies for the fight against age-related cardiovascular disease by boosting CM proliferation.

• DFG Programme: Research Grants