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Student Researchers' Society Topics

Co-supervisor: Dr. FAUST, Zsuzsanna

It is well known that intracellular signaling mechanisms aprticipating in the malignant transformation of the cell. For example the mutant protein coded by the fusion gen bcr-abl is an activated tyrosin-kinase which results in increased phosphorylation on many signaling protein. Despite the recognition of protein O-Glycosylation as a signaling mechanism is a more recent event, it seems to be more and more obvious that it plays a significant role in the development of malignant diseases. During O-Glycosylation, a single N-acetyl-glucosamine molecule is linked to the Ser/Thr residues of proteins. This process can be reversible, can be competing with phosphorylation for the same Ser/Thr sites and occurs on a large scale of various types of proteins. E.g. the proto-oncogen c-myc or the tumor-supressor p53 can both be O-Glycosylated. Interestingly, the cells’ carbohydrate metabolism is associated (in both direction) with O-Glycosylation. Influencing O-Glycosylation (by specific drugs) can impact the glucose uptake of the cells and could be exploited as therapeutic target in malignant diseases.
In this research, our aim is to study the level of protein O-Glycosylation in various malignant hematologic diseases. Characterizing O-GlcNAc levels could be a useful diagnostic marker, but also the basis for developing new therapies.

Many of the chemotherapeutic agents used in the therapy of malignant diseases are cytotoxic due to the inhibition of cell-cycle progress. The concept of the therapy is that malignant cells are usually proliferate more frequently than normal cells thus they are more susceptible to cell-cycle inhibitors. However there are a number of normal cell types in the human body that are also highly proliferating (bone marrow, epithelial cells, fibroblast, etc) thus chemotherapy has severe side-effects.
In this study we explore whether the therapeutic and side-effects of chemotherapeutic drugs could be better separated only by a careful design of the timing of the therapy. Since inhibitors of cell proliferation tend to synchronize cells (road-blocking the cell cycle at a given phase), if we know the exact time of a complete cell cycle for a given cell type, we could choose the best time-window to administer the drug. To achieve this, we aim to develop an MRI method to detect cell-cycle changes in living tissues. 

One of the oldest drug, lithium is still in use in the therapy of bipolar disorder. Since its molecular effects are not completely clarified, it is not known why some of the patients are “lithium responders” while some of them are “non-responders”. According to the literature and our previous results, lithium inhibits (among other enzymes) phosphoglucomutase (PGM). PGM catalyses the reversible conversion of glucose-1-P (Glc-1-P) to glucose-6-P (Glc-6-P). PGM is a key element in the main metabolic pathway of galactose, the lack of (the activity of) PGM results in low efficiency galactose metabolism.
The source of galactose in our food is almost exclusively milk and dairy-products. In our research we aim to explore whether there is a correlation between lithium’s therapy-efficiency and the amount of galactose consumption. Moreover we employ animal models to analyse lithium’s intracellular effect after various amount of galactose/glucose containing food intake.  

Co-supervisor: Prof. Dr. MISETA, Attila

Neuropsychiatric disorders are common and often chronic illnesses imposing severe social and economic burden on our civilized societies. A further complicating issue is that often there are no valid biomarkers that could help us to make the proper diagnosis and to monitor the progression of the disease and the therapeutic response. However, it is important to search for novel, potential biomarkers and this is a field of intense clinical research. The applicant would join to a team of researches doing such clinical research and by that would also get familiar with the current diagnostic tools.

Co-supervisor: Prof. Dr. MISETA, Attila

Adult hippocampal neurogenesis, a once unorthodox concept, has changed into one of the most rapidly growing fields in neuroscience. Numerous factors regulate adult neurogenesis including various neurotransmitters, hormones, stress, physical exercise learning and inflammation. Neurogenesis has been implicated in cognitive function and is stimulated by antidepressant drugs. A lasting reduction in neurogenesis following severe or chronic stress exposure, both in adult or early life, may represent impaired hippocampal plasticity and thus, can contribute to the cognitive symptoms of depression. Our aim is to understand the factors regulating this cellular process and to find novel approaches to stimulate this form of neural plasticity.

Co-supervisor: Prof. Dr. MISETA, Attila

Beneficial health effects of body exercise is common knowledge, however the nature of molecular mechanisms, intracellular processes that are influenced by frequent physical activity are far from completely understood. Exercise could be considered as a type of pre-conditioning; small-scale, controlled stress which induces adaptation mechanisms. The benefit of  preconditioning is that the body is prepared for a potential, more serious stress thus the tolerance level increases, moreover the chance of survival is significantly better.
Previously it was shown that hypoxic preconditioning elevates the level of protein O-Glycosylation which seems to be a beneficial effect for cell survival. Interestingly, O-Glycosylation is strongly linked to carbohydrate metabolism (and consequently, the energetic state of the cells) so it is possible that it is part of an adaptation mechanism that tries to control stress-induced deleterious processes.  In the present study, we aim to clarify whether frequent body exercise increases O-Glycosylation levels on proteins. 

Co-supervisor: Prof. Dr. MISETA, Attila

The 2 main molecular hallmarks of Alzheimer’s disease are the senile plaques (β-amyloid peptides) and neuro-fibrillary tangles (hyperphosphorylated tau proteins). Several studies demonstrated that chronic hypoglycemia that occurs more frequently in elderly people might be an significant cause of the disease. Due to lower glucose levels in the neurons, several post-translational modification requiring carbohydrates might change. E.g. O-Glycosylation, which competes for the same sites on protein with phosphorylation will be down-regulated, thus enabling tau proteins to be hyperphosphorylated. The ER stress and the so called “unfolded protein response” (UPR) is also associated with Alzheimer’s, which might be the consequence of aberrant N-glycans on both β-amyloid and tau.
The aim of the study is to better identify the various protein post-translational modifications that are altered due to hypoglycemia. Moreover, it is necessary to explore the impact of these changes on cellular functions such as viability, morphology, proliferation, etc. Lastly, the long term aim of the study is to find diagnostic markers that predict the development of Alzheimer’s at an early stage.  

The purpose of the study is the quantitative and structural analysis of circulating exosomal miRNA fraction from body fluids using quantitative real-time PCR platform. Many genes are subject of miRNA regulation, thus the recognition of extracellular miRNA (circulating miRNA) in biological fluids has generated an interest for their potential use of markers for progressive human diseases. These molecules have emerging role as liquid biopsy-based markers. Principally our research focuses on serum and saliva miRNA expression analysis compared to tissue expressions in head and neck cancer.     

The purpose of the study is the quantitative and structural analysis of circulating exosomal miRNA fraction from body fluids using quantitative real-time PCR platform. Many genes are subject of miRNA regulation, thus the recognition of extracellular miRNA (circulating miRNA) in biological fluids has generated an interest for their potential use of markers for progressive human diseases. These molecules have emerging role as liquid biopsy-based markers. Principally our research focuses on serum and saliva miRNA expression analysis compared to tissue expressions in head and neck cancer.     

The protein post-translational modification called O-Glycosylation (or O-GlcNAc) is a special process; in contrast to N-glycosylation, O-GlcNAc is reversible, occurs in the cytoplasm and in the nucleus, and similarly to phosphorylation, targets Ser/Thr side-chains of the proteins. More than 500 proteins has been shown so far to carry an O-GlcNAc moiety. It is involved in the regulation of several intracellular mechanism; carbohydrate metabolism, cell cycle, malignant transformation, etc.
It has been shown that O-GlcNAc is increased upon stress which seems to be a natural adaptation mechanism helping the cells’ survival. Blocking O-GlcNAc by inhibitors caused lower viability and increased apoptosis, following stress such as hypoxia or heat shock. The aim of this study is to characterize the dynamic change of O-GlcNAc level and its impact on cell survival in neuronal cells and in the brain tissue of experimental animals. Learning more about O-GlcNAc’s role in the adaptation of neuronal cells could help to improve therapeutic strategies in brain injuries including stroke.  

Co-supervisor: Prof. Dr. MISETA, Attila

Stress appears to be increasingly present in our modern, and demanding, industrialized society. Virtually every aspect of our body and brain can be influenced by stress and although its effects are partly mediated by powerful corticosteroid hormones that target the nervous system, relatively little is known about when, and how, the effects of stress shift from being beneficial and protective to becoming deleterious. Decades of stress research have provided valuable insights into whether stress can directly induce dysfunction and/or pathological alterations, which elements of stress exposure are responsible, and which structural substrates are involved. Our aim is to understand the neuropathological and molacular changes in response to stress in different CNS structures.

Co-supervisor: Dr. NAGY, Tamás

The occurrence of bipolar disorder is about 1.2% for both sexes worldwide. Lithium is a frequently employed mood-stabilizer eventhough the exact molecular mechanism of its action is not known. One of its effects is replacing magnesium on proteins, including the enzyme called phosphoglucomutase (PGM). PGM, which is a key enzyme in galactose and glycogen metabolism, catalyses the reversible conversion of glucose-1-P (Glc-1-P) to glucose-6-P (Glc-6-P).
Interestingly, alterations in PGM activity also impact intracellular calcium regulation. We have shown earlier in a S. cerevisiae model that inhibiting PGM by lithium increased intracellular calcium storage, but decreased the calcium signals in excited cells. In the present study we will investigate the link between metabolic changes (PGM inhibition) and calcium regulation. According to our hypothesis and our preliminary results, the role of endoplasmic reticulum and protein post-translational modifications are key elements in this process.   

Co-supervisor: Dr. NAGY, Tamás

Cellular volume regulation is one of the key functions that define any living cells. It affects and interacts many physiological process, including membrane traffic, cell migration, cell proliferation, adaptation to stress and environmental challenges. Despite this, volume regulation is often overlooked process and there are still many questions to be answered, related to both it's regulatory mechanisms and it's effect on other cellular functions.
The shape of the cells and the amount and organization of intracellular water is regulated by proteins. Since translated proteins can’t change their amino-acid sequence, post-translational modifications play an improtant role in the dynamic regulation of water. Phosphorylation, ubiquitination, glycosylation, binding of smaller molecules (ATP, GTP, cAMP, lipids), bindig to ions can all change the configuration and the hydorophobic properties of the proteins.
Previously we showed that increased O-Glycosylation of proteins can alter the osmotic resistance and the intracellular water diffusibility of the cells. In this study, our aim is to clarify the exact mechanism by which O-Glycosylation inflences water regulation; whether is it a) changing the hydrophobicity, b) changing the function of some specific proteins involved in volume regulation (aquaporin e.g.) or c) influencing signaling pathways.