Head Prof. Dr. rer. nat. Theresia Kraft
Hannover Medical SchoolMolecular and Cell Physiology, OE 4210
Building: I3, Block: 1, Level: 03
Carl-Neuberg-Str. 130625 HanoverGermany
Prof. Dr. rer.nat Theresia KraftE-Mail: Power.TheresiaMH-Hannover.de
Katrin Fuchs, Phone: 0511 / 532-6396, Fax: 0511 / 532-4296 E-Mail: Fox.Katrin.mzpMH-Hannover.de
General information and research profile
The Institute of Molecular and Cell Physiology deals with the molecular functional principles of so-called motor proteins.
These drive a large part of the known movement and transport processes. These include intracellular transport processes, changes in the shape of cells as well as various types of locomotion of cells or entire organisms. Motor proteins from three families are responsible for the diversity of transport and movement phenomena. Myosins interact with actin filaments, dyneins and kinesinesines generate forces and movements in interaction with microtubules. In recent years, the importance of such motor proteins for various diseases has become the focus of the Institute’s interest. Diseases caused by changes in the motor proteins themselves or in associated proteins include hypertrophic cardiomyopathy (HCM), degenerative diseases of the motoneurons, Alzheimer’s dementia or tumor metastasis.
Our goal is to elucidate how mutations in motor proteins or associated proteins alter the molecular functional principles of motor proteins and lead to corresponding clinical pictures. One focus is the elucidation of direct functional effects of point mutations in the β-kardialen heavy chain of myosin 2, which lead to the picture of hypertrophic cardiomyopathy (HCM). The elucidation of direct functional effects of HCM-associated mutations can on the one hand open up starting points for corrective influence on primary dysfunctions and the resulting clinical picture, and on the other hand allow insight into the molecular functional principles of motor proteins.
The current main focus is on how different point mutations, also in other sarcomeric and non-sarcomeric proteins, can lead to the phenotype of familial hypertrophic cardiomyopathy. Our observation that functional changes in the myocardium of affected patients caused by HCM-associated point mutations are very differently pronounced from cell to cell was indicative. Some cells even show fully normal behavior as if no mutated protein was expressed in these cells. In the meantime, we have been able to show that a different proportion of mutated mRNA is expressed from cell to cell according to this functional variance. Some cells express almost exclusively wild-type mRNA, while other cells express almost exclusively mutated mRNA. The resulting functional variability between adjacent cardiomyocytes in the cellular network of the myocardium leads to distortions in the tissue structure leading to the FHC-typical cellular and myofibrillary disarray with fibrosis and hypertrophy.
In the meantime, we have been able to show that the cause of cell-to-cell variability in the proportion of mutant protein is probably due to the fact that mutant and wild-type alleles are transcribed independently of each other in random bursts. First tests confirm this hypothesis, with which we can quantitatively explain the entire spectrum of our data collected so far (by model calculation). This concept suggests that any mutation in a sarcomeric or non-sarcomeric protein (e.g. kinases) that leads to a functional change in the sarcomere leads to a functional imbalance between individual cardiomyocytes via such a random, burst-like transcription and can thus trigger the phenotype of a hypertrophic cardiomyopathy.
In our previous investigations we were limited to myocardial samples from myectomies or explants of affected FHC patients. To address longitudinal studies on the pathogenesis of FHC and to investigate mutations for which we do not have access to patient samples, we are currently establishing three approaches: differentiation of cardiomyocytes via induced pluripotent stem cells from skin fibroblasts of affected patients, expression of cardiac myosin head domains in a human ventricular cell line, and development of an animal model (pig) that allows us to follow the development of the FHC phenotype in detail.