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Determination of mutation spectrum and frequency representation of variants in genes involved in Melanocortin Receptor Type 4 Signaling Cascade (MC4R)
Toman, Izabela ; Včelák, Josef (advisor) ; Aldhoon Hainerová, Irena (referee)
This master's thesis is focused on determination of mutation spectrum and frequency representation of variants in genes involved in Melanocortin Receptor Type 4 Signaling Cascade. Mutation in genes connected to MC4R signalisation cascade may induce so called monogenic type of obesity, which is characterised not only by mutation in single gene but also by an early onset severe obesity and hyperphagia. Due to new means of medications being introduced its especially important to ascertain the frequency of mutations in Czech children and adolescent population. Theoretic part of the thesis is devoted to description of energy homestasis and leptin- melanocortin pathway. Physiology of hunger and satiety and the most common causes of obesity and monogenic obesity are also included. There is also mention of population differences in genetical predisposition for monogenic obesity namely in genes MC4R, POMC, SIM1 and BDNF which were the focal points of this thesis. In practical part, genetical analysis of 1910 samples from Czech children and adolescent population was implemented. We identified twelve different, likely pathogenic causal variants via next generation sequencing. More precisely eight different MC4R variants, 2 POMC variants and 2 SIM1 variants. In those, two novel variants were found c.346 C> T...
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Role of Islet1, BDNF and nanoparticles in development, function and regeneration of the auditory system
Chumak, Tetyana ; Syka, Josef (advisor) ; Druga, Rastislav (referee) ; Maršálek, Petr (referee)
Detailed knowledge of the role that particular genes and factors play during the development and in the normal function of the auditory system is necessary to develop successful regenerative inner ear therapies. Islet1 transcription factor and brain derived neurothrophic factor (BDNF) have great potential to play a role in regenerative inner ear therapy as both have been shown to be sufficient for self-repair regeneration in cochlea in animal studies. In this study we looked at the roles these two factors play in the development and function of the auditory system. In the transgenic mice used in the study, overexpression of Isl1 affected cell specification during embryonic development, leading to enlargement of the cochleovestibular ganglion and accelerated nerve fiber extension and branching in mutant embryos. The hearing of young transgenic mice was not affected. However, it started to decline in 1-month-old animals. This early onset of age-related hearing loss was found to be a consequence of the neurodegeneration of the olivocochlear system caused by Pax2-driven Isl1 misexpression in the hindbrain. Our data provide the first evidence that the alternation of the olivocochlear system efferent system accelerates the age-related functional decline of hearing without the loss of OHCs. The functional role of...
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Role of Islet1, BDNF and nanoparticles in development, function and regeneration of the auditory system
Chumak, Tetyana ; Syka, Josef (advisor) ; Druga, Rastislav (referee) ; Maršálek, Petr (referee)
Detailed knowledge of the role that particular genes and factors play during the development and in the normal function of the auditory system is necessary to develop successful regenerative inner ear therapies. Islet1 transcription factor and brain derived neurothrophic factor (BDNF) have great potential to play a role in regenerative inner ear therapy as both have been shown to be sufficient for self-repair regeneration in cochlea in animal studies. In this study we looked at the roles these two factors play in the development and function of the auditory system. In the transgenic mice used in the study, overexpression of Isl1 affected cell specification during embryonic development, leading to enlargement of the cochleovestibular ganglion and accelerated nerve fiber extension and branching in mutant embryos. The hearing of young transgenic mice was not affected. However, it started to decline in 1-month-old animals. This early onset of age-related hearing loss was found to be a consequence of the neurodegeneration of the olivocochlear system caused by Pax2-driven Isl1 misexpression in the hindbrain. Our data provide the first evidence that the alternation of the olivocochlear system efferent system accelerates the age-related functional decline of hearing without the loss of OHCs. The functional role of...
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