Analysis of common denominators in cilia-dependent congenital heart defects

• Applicant: Professorin Dr. Melanie Philipp
• Subject Area: Pharmacology ; Cardiology, Angiology
• Term: since 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 252863006

Congenital heart defects (CHD) still remain the most common malformation diagnosed in newborns as well as unborn fetuses. CHDs can be deleterious and often require surgery within the first days of life. Many endeavors have thus been undertaken to decipher molecular causes of CHDs. For instance large-scale sequencing approaches of up to 10,000 patients have been carried out and several hundred genes have been identified as indispensable factors during cardiogenesis. Those sequencing approaches, however, have also led to the conclusion that unrealistically large numbers of patients would be required for decisive identification of all genes involved in faithful heart development. In my lab we make use of alternative approaches to uncover molecular processes triggering CHDs. One chosen avenue is the identification of common denominators. These may be fundamental metabolic processes on which signaling pathways converge or even subcellular structures per se. The cilium likely is such a common denominator for the developing heart. Cilia guide a plethora of signaling and developmental processes. Furthermore, cilia deficiencies lead to a large number of disorders collectively called ciliopathies. A prominent example is heterotaxy, in which early left-right (LR) asymmetry development is disrupted leading to random arrangement of inner organs. The majority of heterotaxy patients notably also suffers from severe CHDs. Moreover, a growing number of scientists argues that CHDs without LR asymmetry defects arise from faulty cilia, too. In the previous funding period, we have discovered the mitochondrion as major regulator of ciliogenesis. CHD patients with CHD more often carry deleterious genetic variants of mitochondria proteins than patients with unrelated afflictions. How precisely mitochondria impact on ciliogenesis, however, remains to be elucidated and will be the focus of the subsequent funding period.

• DFG Programme: Research Grants