Research Summary:
The investigation of molecules and their signalling in the process of muscle regeneration and differentiation has an important role in the developmental biology and medicine; helps to reveal the pathomechanisms and therapeutic possibilities of muscle diseases. Skeletal muscle has a remarkable capacity to regenerate after injury or in muscle diseases (e.g. muscle dystrophies). The basis of the skeletal muscle regeneration is the activation and proliferation of the precursor (satellite) cells, followed by the fusion of myoblast into multinucleated myotubes during the process of differentiation.
The TGF-beta family member myostatin is a potent negative regulator of skeletal muscle mass by inhibiting the proliferation and differentiation of myoblasts. Beside its autocrine-paracrine effect on skeletal muscle, as an endocrine factor it has systemic metabolic effects, as well. Naturally occurring mutations of the myostatin gene (e.g. in human, cattle, Compact mice) or silencing myostatin gene in knock out mice led to a dramatic increase in skeletal muscle mass. In the contrary, its increased expression manifested in loss of skeletal muscle weight in cases of aging, immobilization, chronic heart failure, muscle dystrophies or cancer cachexia. The precursor promyostatin is cleaved into propeptide and active myostatin fragments in the Golgi network or extracellular matrix, hereby localizing of ligand activity by extracellular localization of maturation. The myostatin signalling is regulated by myostatin binding proteins and other matrix components, as well.
The members of Rho family of small GTPases (Rac1, Rho and CDC42) play an important role in muscle differentiation. They are essential during several cellular processes regulating the organization of actin cytoskeleton, cell polarity and cell cycle. The active RhoA increases the expression of the myogenic regulatory factor MyoD and myogenin, while elevated Rac1 activity required for the process of myoblast fusion.
One of the cell markers of the muscle progenitor satellite cells is the type-I transmembrane heparan-sulfate proteoglycan syndecan-4. The precise role of syndecan-4 in muscle development is not known yet; however, the muscle morphology and regeneration is damaged in syndecan-4-/- mice, and they are deficient in satellite cell activation, proliferation, and myoblast differentiation. The extracellular domain of syndecan-4 interacts with matrix components, growth- and other factors. Syndecan-4 can function as a link between the extracellular matrix and the cytosol; therefore, it can play an important role in the outside-in and inside-out signalling influencing cell adhesion and cell division. Moreover, syndecan-4 can down-regulate the activity of Rac1.
Our aim is to investigate the signal transduction of myostain using in vitro and in vivo model systems, and to unravel the molecular mechanism of muscle differentiation. We aimed to analyze the role of syndecan-4 in the promyostatin/myostatin pathway and in the regulation of the activity of Rho GTPases during muscle differentiation using a wide variety of biochemical, histochemical and cytochemical methods.
Required language skills: English Further requirements: TDK munka
Number of students who can be accepted: 1
Deadline for application: 2019-06-15
2024. IV. 17. ODT ülés Az ODT következő ülésére 2024. június 14-én, pénteken 10.00 órakor kerül sor a Semmelweis Egyetem Szenátusi termében (Bp. Üllői út 26. I. emelet).
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