Defining the role of KLF15 in regulation of the Wnt Signaling in the healthy and diseased heart

• Applicant: Professorin Dr. Laura C. Zelarayan-Behrend
• Subject Area: Pharmacology ; Cardiology, Angiology
• Term: from 2010 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 158888035

Cardiac remodeling is accompanied by a re-activation of fetal genes driving cardiac development, which so far has unclear pathophysiological relevance. In this context, the Wnt/beta-catenin pathway plays distinct time-specific roles during cardiac development. Whereas less activation is found in the adult myocardium under physiological conditions, it appears to be activated in cardiac remodeling. Thus, elucidation of this pathway may uncover novel cardiac specific target as basis for new therapeutic concepts to prevent the onset of heart failure. Our previous data suggest that regulation of the canonical Wnt signaling plays an important role in cardiac homeostasis and remodeling. Importantly, tissue-specific regulators of the ubiquitous Wnt pathway, enhancing or repressing target gene expression, are critical to modulate downstream gene transcription specifically in a desired cell type. In line with this concept, we previously identified the Krueppel-like factor (KLF) 15 as a nuclear beta-catenin/TCF4 interaction partner exerting transcriptional inhibition of the Wnt pathway specifically in the heart. Based on this finding, we will further investigate the nuclear Wnt transcriptional regulation in cardiac cells. We will specifically test the hypothesis that KLF15 assembles a specific cardiac Wnt complex modulating gene transcription important for maintaining normal heart homeostasis, relevant in human cardiac tissue. This hypothesis will be tested by (1) elucidation of the molecular components of the KLF15/TCF4 complex; (2) characterization of the cardiac KLF15-depedent gene regulation and function in the ischemic mouse heart; and (3) molecular and functional characterization of KLF15 in human engineered heart muscle (EHM). This study will define an early molecular signature in heart tissue of Klf15 KO related to cardiac deterioration as well as identify gene regulatory networks depending on KLF15 in human heart muscle. Moreover, we will extend our finding on the role of KLF15 in cardiac cells in the murine system to the human system by exploiting recently established transgenic engineered human myocardium model. This study will add the understanding of a specific cardiac nuclear regulation complex to the classical Wnt transcriptional cascade and identify cell specific regulatory modules with novel function in cardiac homeostasis. This knowledge will serve a basis for the development of novel pharmacological approaches for antagonizing heart failure progression.

• DFG Programme: Research Grants