Thesis supervisor: Mátyás Mink
Location of studies (in Hungarian): Univ. Szeged, Faulty of Medicine, Dept. of Med. Biology Abbreviation of location of studies: ÁOK
Description of the research topic:
The type IV network-forming collagens are components of the basement membrane at the highest molar ratio. The proteins are encoded by three head-to-head aligned gene pairs in mammals. Mutations in the human COL4A3, -A4 and A5 genes are etiologic factors in development of Alport syndrome. The proteins express in the eye, ear and kidney, cause organ-specific disease, manifested in blindness, deafness and end-stage renal failure. The ubiquitous basement membrane, containing the COL4A1 and COL4A2 proteins, is found throughout the body, located at the basal side of the epithelial-endothelial cells, surrounds unique skeletal muscle fibers, Schwann cells and adipocytes also. Mutations in genes of these proteins cause systemic disease, covering vascular instability, porencephaly, kidney failure, ophthalmic complications and muscular dystrophy.
Inherited diseases of muscle are the clinically and genetically heterogeneous myopathies, including the degenerative changes of the muscle fibers, muscular dystrophies (ICD-10: G72.0 - G72.2). The root of hereditary muscular dystrophies are often mutations in the proteins of the sarcoplasm - extracellular matrix axis (dystrophin, collagen IV, VI collagen, integrin, laminin) that disrupt the linkage. Mechanistically, the load generated by the muscle fibers during contraction is not transferred properly toward the extracellular space, erroneous mechano-transduction occurs, as we have proven in our Drosophila model.
We identified an allelic series in the Drosophila col4a1 gene. All mutations are G-> A transitions affecting glycine triplets, a critical amino acid in the correct spatial structure of collagens, resulting in aspartic acid, glutamic acid and serine substitutions. Based on our research the mutations cause systemic disease also, affecting the epithelial cells of Malpighian tubules, the digestive system and the muscles. We recorded oxidative damage, mitochondrial disorder, fiber size heterogeneity, formation of actin aggregates, fiber degeneration within the muscle, consistent with the onset of muscular dystrophy.
Recent research suggests overlapping pathomechanisms between the irreversible skeletal muscle loss sarcopenia, manifested from the fourth decade, and muscular dystrophy, both characterized by mitochondrial dysfunction, increased cell death, elevated concentration of reactive oxygen radicals and by accumulation of insoluble cytoplasmic protein aggregates. Thus, any therapeutic process effective in the treatment of either sarcopenia or muscular dystrophy is expected to alleviate the symptoms in both cases, relieving significantly the burden of the health care systems. We thus aim at performing pre-clinical studies by the use of our model to identify pharmacologic approach able to mitigate the symptoms of these serious conditions and to create the basis of human therapy.
Required language skills: English Further requirements: TDK munka
Deadline for application: 2018-02-28
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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