Bridging the gap between cardiac and vascular regeneration

Turan B. (Yürütücü)

AB Destekli Diğer Projeler, 2024 - 2027

Cardiac regeneration in adult mammals is an extremely inefficient process. Massive

cardiomyocyte and vascular loss results in a permanent decline of contractile function. Our

team has contributed to understanding the mechanisms that halt cardiomyocyte proliferation

after birth and developed therapeutic strategies to promote cardiac regeneration by either

delivery of RNAs or mechanical unloading. So far, attempts at regenerating the cardiac muscle

have not considered the need to simultaneously induce adequate vascularization of the newly

formed myocardium.

RESCUE has the ambition to develop innovative RNA therapies to simultaneously induce

cardiomyocyte proliferation and angiogenesis, and thus to regenerate both the muscular and

vascular components of the heart after cardiac damage. Toward this goal, we will explore two,

non-mutually exclusive hypotheses. The first hypothesis is that any treatment promoting

cardiomyocyte proliferation, which depends on their partial de-differentiation, is sufficient to

elicit, in turn, an angiogenic response. This hypothesis is based on our preliminary data,

showing that adult, fully differentiated cardiomyocytes inhibit angiogenesis in the heart. The

second hypothesis is that cardiomyocyte proliferation needs to be complemented by a proangiogenic

therapy, to provide adequate trophic support to the regenerating myocardium. Also

in this case, we will leverage our preliminary data to validate existing candidates and to identify

novel molecules that can be overexpressed to stimulate effective cardiac angiogenesis. The

most effective molecules inducing both cardiomyocyte proliferation and vascular growth will be

produced as RNA therapeutics and encapsulated into lipid nanoparticles, optimized to target

the myocardium. The final products will be validated for their therapeutic potential in mouse

models of cardiac ischemia.