Přehled
Supervisor
Martin Gregor
Project description
Plectin is a key cytoskeletal crosslinker required for mechanical stability and signaling in skeletal muscle and heart. Mutations in the plectin isoform P1f cause limb-girdle muscular dystrophy accompanied by progressive cardiomyopathy. Due to the large size of full-length plectin, classical gene-replacement strategies are not feasible, necessitating alternative therapeutic approaches.
This PhD project focuses on the development and functional characterization of mini-plectins engineered plectin variants retaining essential functional domains while being compatible with AAV-mediated gene delivery. The main objective is to evaluate their capacity to restore cytoskeletal organization and function in muscle and cardiac cells.
In the in vitro part, the student will analyze expression, localization, and functional integration of miniplectins in cultured cardiomyocytes. Using advanced fluorescence microscopy and biochemical approaches, the project will assess the ability of mini-plectins to reconstitute cytoskeletal networks, cell–cell junctions, and mechanosensitive signaling pathways impaired by P1f deficiency.
In the in vivo part, the therapeutic potential of mini-plectins will be tested in a newly established P1f knockout mouse model that recapitulates key features of human disease. AAV-mediated delivery will be evaluated for its ability to rescue pathological alterations in skeletal muscle and heart using histological, immunofluorescence, and functional readouts. The project will be conducted in close collaboration with international experts in gene therapy and muscle pathology.
This project combines mechanistic cell biology with translational gene-therapy approaches and aims to provide proof-of-concept data for mini-plectin–based therapies for plectin-related muscle and cardiac disease.
Candidate profile
Master’s degree in molecular or cell biology, biomedical sciences, or a related field
Strong interest in muscle, cytoskeletal, or cardiovascular biology
Motivation to work with cell culture, microscopy, and mouse models
Ability to work independently and in a collaborative research environment
Good organizational and communication skills
Suggested reading
Crudele J. M., Chamberlain J. S.: AAV-based gene therapies for the muscular dystrophies. Hum Mol Genet 2019 28(R1):R102-R107.
Prechova M, Korelova K, Gregor M: Plectin. Curr Biol 2023 33(4): R128-R130.
Gundesli H., Talim B., Korkusuz P., Balci-Hayta B., Cirak S., Akarsu N. A., Topaloglu H., Dincer P.: Mutation in exon 1f of PLEC, leading to disruption of plectin isoform 1f, causes autosomal-recessive limb-girdle muscular dystrophy. Am J Hum Genet 87(6):834-41.
Prechova M, Adamova Z, Schweizer AL, Maninova M, Bauer A, Kah D, Meier-Menches SM, Wiche G, Fabry B, Gregor M: Plectin-mediated cytoskeletal crosstalk controls cell tension and cohesion in epithelial sheets. J Cell Biol 2022 221(3):e202105146.
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