Thesis supervisor: Hargita Hegyesi
Location of studies (in Hungarian): SE Abbreviation of location of studies: SE
Description of the research topic:
In modern societies, the most common causes of death are cardiovascular diseases. In addition to state-of-the-art medical care, late-onset pathological changes irreversibly impair patients' quality of life and weigh enormous burdens on the health care system. Early detection and prevention means that patients receive timely individual therapeutic support that can still be able to restore harmful cellular biological processes. To do this, however, it is necessary to know early-cell cell biological markers, which, by rearranging the molecular network, indicate the stress states in time. Molecular diagnosis offers unlimited potential for finding such new biomarkers with the spread of high-throughput measurement options (microarray, complete genome sequencing, proteomics, etc.) (1). The markers for myocardial cell death include troponins, creatine kinases, NT-proBNP (2), PAI-1, galectin-3, and inflammatory markers (3.4), but there is no consensus on the use of markers and their specificity is an open question.
Extracellular vesicles (EVs) are membrane-bound heterogeneous structures derived from cells. Their size is varied and the smallest vesicles have a diameter of approx. 30-50 nm, while the largest can be several micrometers. Their production appears to be a general cellular biological phenomenon, similar to intracellular transport, cellular movement, or programmed cell death (5). It in known that all the cells examined so far (be it bacteria (6) or higher-order animal cells) produce a variety of vesicles, so that vesicular production can be seen as an evolutionally conserved adaptive cellular response (7).
The intense research of EVs began 10 years ago, and it was not obvious a few years ago what exactly these structures are - and their isolation and identification are still surprisingly difficult today. We do not know the details how different vesicular populations relate to what mechanism they produce and how they affect cell-cell communication. The methods of isolation and detection essential for laboratory testing are diverse, and the methods for testing vesicles are poorly standardized.
In our work group we have set up heart disease models and characterization of cardiomyocyte-derived vesicles.
We established primary cultures to isolate EVs, from which the EVs can be isolated from the supernatant. A stable primary culture can be maintained from a newborn mouse for up to two to three weeks, thus modeling cardiac damage in vitro (8). In vivo cardiovascular damage can only be modeled in an adult animal; therefore, a cardiomyocyte culture isolated from an adult animal is also set up to isolate extracellular vesicles (EV) and to find a vesicular marker characteristic of heart damage. Animal studies are only planned if the systemic character of cardiovascular disease cannot be modeled with in-vitro cell cultures.
Our hypothesis is that extracellular vesicles mediate inflammatory responses, thereby affecting the regeneration ability of the cells.
Research topics:
• We investigate the mechanism of action of miR sponges delivered in vesicles in cardio-pulmonary cell communication.
• In a transgenic murine model (expressing myocardial-specific fluorescent protein Cre recombinase) we can investigate the lack of a gene in cardiomyocyte-derived vesicles. In induced myocardial infarction, we want to identify the participants in the heterogeneous vesicle population in monocyte / macroscopic differentiation.
• The cardioprotective role of GDF-15 in the inflammatory response and in the EV transfer
The research of extracellular vesicles is not only exciting for cell biology and physiology, but may also be of great medical use: they can be discovered by pathophysiological processes not known so far, new types of biomarkers can be found, and ultimately it is no exaggeration to claim - from a physiological nucleic acid transfer system that is, their application can open up new horizons towards nanotherapy.
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