Pathomechanistic role of IGF2BP2 in myocardial infarction: induction of remodeling and cardiac hypertrophy

• Applicant: Professorin Dr. Sonja Keßler
• Subject Area: Cardiology, Angiology ; Pharmacy
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 452379776

Myocardial infarction is characterized by an undersupplying of the heart with oxygen leading to necrosis of the infarcted area. After myocardial infarction an endogenous process starts, which is called ventricular remodeling. With remodeling the body tries to fix the tissue damage, but thereby induces scarring of the heart tissue. Thus, remodeling leads to changes of heart shape, size, and elasticity, which can worsen cardiac output. Adverse ventricular remodeling as a consequence of loss of viable myocardium, exuberant inflammatory response, and neurohormonal activation may lead to negative prognostic implications.The family of Insulin-like growth factor 2 (IGF2) mRNA binding proteins (IGF2BPs/IMPs/VICKZ proteins) are RNA binding proteins that regulate their RNA targets through a variety of mechanisms. The three proteins have been shown to regulate, in various systems and cell types, intracellular RNA localization, RNA stability, RNA translation, and alternative splicing. Aim of this project is to test the hypothesis that IGF2BP2 overexpression, induced during MI, can lead to remodeling and/or DCH, most likely through the regulation of a specific set of target RNAs. We propose to test these hypotheses directly using both genetic approaches and neonatal primary cardiomyocytes (pCMs), allowing us to follow both the morphological and physiological effects of IGF2BP2 overexpression, while also being able to identify the molecular basis for the effects. The following aspects will be investigated in order to test the hypothesis:- Characterization of IGF2BP2 expression in normal and stressed hearts - Identification of RNAs and proteins up- and down-regulated in vivo as a result of IGF2BP2 expression.- Relevance of lipotoxicity in hearts overexpressing IGF2BP2This project will provide new insights into the pathomechanisms of remodeling and dilated cardimyopathy. This might help to improve patient prognosis and therapy.

• DFG Programme: Research Grants
• International Connection: Austria, Israel
• Cooperation Partners: Professor Dr. Johannes Haybäck; Professor Dr. Gerhard Pölzl
• International Co-Applicant: Professor Dr. Joel K. Yisraeli