Die Rolle von Plectin im gesunden und erkrankten Herzen

• Antragsteller: Professor Dr. Rolf Schröder
• Fachliche Zuordnung: Kardiologie, Angiologie ; Biochemie ; Zellbiologie
• Förderung: Förderung seit 2022
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 501841349

Wider research context: Plectin is a cytoskeletal linker protein with a multitude of cellular functions. Its pivotal role in mechanical stress-bearing tissues in humans is highlighted by the fact that mutations in the human plectin gene (PLEC) cause a variety of skin and skeletal muscle diseases. The group of human plectinopathies thus far comprises five autosomal-recessive disorders, namely epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), EBS-MD with myasthenic syndrome (EBS-MD-MyS), limb girdle muscular dystrophy type 2Q (LGMD2Q), EBS with pyloric atresia (EBS-PA), and skin-only EBS, as well as the autosomal-dominant variant EBS-Ogna. Plectinopathies belong to the group of rare diseases with an incidence of less than 5 affected individuals in 10,000. Beyond skin and skeletal muscle involvement, PLEC mutations also cause a broad spectrum of cardiac disease manifestations. However, very little is currently known about the role of plectin and its individual isoforms in normal and diseased hearts.Objectives: 1) How does plectin deficiency impact on the cardiac function, morphology and biochemistry? 2) How do acute strenuous physical activities impact on the cardiac pathology in plectin knock out (KO) mice? 3) What is the functional role of the four major plectin isoforms in cardiac muscle tissue and cardiomyocytes? 4) Can selected drugs ameliorate the cytoskeletal and mitochondrial pathology in plectin-deficient human cardiomyocytes?Approach: We will apply a multilevel experimental approach to address our goals: in vivo studies on plectin KO mice will comprise treadmill running, echocardiography, standard and long-term electrocardiogram. Explanted hearts will be studied by light-, immunofluorescence-, and electron microscopy, immunoblotting, blue native gel electrophoresis and PCR analyses. Plectin isoform related functions will be tackled by studies in isoform-specific KO mice and cardiomyocytes. Plectin-deficient human induced pluripotent stem cells will be the experimental basis for the evaluation of cell protective effects of two orphan drugs, which have a promising therapeutic potential. Innovation: We strongly believe that our project will open a completely new chapter in our current understanding of the role of plectin and plectin isoforms in normal and diseased cardiac tissue. Beyond deeper insights into the pathophysiology of plectin-related cardiac diseases, the outlined project shall answer the question if, and to what extent, physical activity and the two chosen drugs can alter the cardiac muscle pathology in KO cells and mice. Thus, our work also has the translational potential to improve the clinical counseling of patients and may help to pave the way towards new treatment options for plectinopathies. Primary researchers involved: Dr. Lilli Winter, Medical University of Vienna & Prof. Dr. Rolf Schröder, University Hospital Erlangen

• DFG-Verfahren: Sachbeihilfen
• Internationaler Bezug: Österreich
• Kooperationspartnerin: Dr. Lilli Winter