The role of PRDM16 in cardiac development, a novel therapeutic target for heart failure

• Applicant: Dr. Anne-Karin Kahlert
• Subject Area: Pediatric and Adolescent Medicine ; Developmental Biology
• Term: from 2013 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 251134136

Dilated cardiomyopathy (DCM) is the most common cardiac diagnosis of all cardiomyopathies. The prevalence is about 1:2500. DCM may occur at a wide range of ages, but is most prevalent in the 3rd or 4th decade with an additional peak in young children. Left ventricular noncompaction cardiomyopathy (LVNC) is a common feature in early embryopathy in humans and has recently been classified as a distinct primary cardiomyopathy with a genetic etiology. LVNC as well as DCM have been associated with a number of genetic syndromes. Chromosome 1p36 deletion syndrome is the most common terminal deletion syndrome in humans, occurring 1 in 5000 births. A substantial proportion (23-27%) of individuals with del1p36 syndrome have cardiomyopathy which may occur in the presence or absence of structural heart disease. Quite recently our working group described the loss of a gene within the deletion that is responsible for the cardiomyopathy associated with monosomy 1p36, and confirmed its role in non-syndromic LVNC and DCM. Detailed multi-allelic mapping in del1p36 syndrome identified loss of PRDM16 as underlying the cardiomyopathy in this syndrome. Modeling of PRDM16 haploinsufficiency and a human truncation mutant in zebrafish resulted in impaired cardiomyocyte proliferation with associated physiologic defects in cardiac contractility and cell-cell coupling. Using a phenotype-driven screening approach in the fish, we identified 5 compounds that rescued the physiologic defects associated with mutant or haploinsufficient PRDM16. The approach of this study will be to elucidate the role of PRDM16 in cardiac development as well as its function as a novel therapeutic target. We therefore want to explore the signaling pathway of PRDM16 in the heart using established zebrafish models and in vitro experiments. Using DNase I hypersensitivity sites and DNase-Seq approach in a murine cardiomyocyte cell line we want to identify new interaction partners of PRMD16. Performing RNA-Seq will characterize the global pattern of gene expression in PRDM16 mutant and wildtype zebrafish hearts. Next we will investigate the role of PRDM16 in cellular proliferation responses in adult zebrafish regeneration. Different zebrafish models will therefore undergo either cryoablation or apical resection to examine if loss of PRMD16 alters proliferation in a regenerating heart. Using our zebrafish model as a personalized disease model we will create a high-throughput screen and examine specific pathways, accelerate the exploration of disease biology and develop innovative therapeutic approaches. To explore the underlying mechanism of the identified 5 compounds we will use both a computational approach querying databases and perform biochemical affinity purification to identify the binding partners. With this research proposal we want to point out the importance of having a personalized disease model for identifying novel targets for therapeutic interventions.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Calum MacRae