« Research

Student Researchers' Society Topics

Co-supervisor: Dr. POZSGAI, Gábor

The treatment of the chronic inflammatory diseases, like allergic dermatitis and inflammatory bowel diseases (IBD) means still a problem of modern medicine. In the progression of these diseases neurogenic factors play an important role. Neuropeptides released from the capsaicin-sensitive sensory neurons, as well as inflammatory and immune cells influence the inflammatory processes, but their complex roles have not been cleared in precise details. Some of these peptides exert proinflammatory (SP, NKA, CGRP), while others exert antiinflammatory effects (opioid peptides, somatostatin, cortistatin, PACAP). Beside the classical peptide mediators of neural origin, hemokinin-1 and endokinins, expressed mainly in inflammatory and immune cells, were discovered a few years ago. All these peptide mediators are released on response to endogenous or exogenous stimuli, through the activation of Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1), or independently of that. Antagonising the effect of the proinflammatory peptides, as well as the precise identification of the mechanisms of antiinflammatory mediators may enable the development of antiinflammatory drugs acting on new target structures. Therefore, our experiments aim to investigate the interactions between the neurogenic components and the immune system in animal models of dermatitis and IBD, with the help of functional, morphological, immunological, molecular biological, as well as in vivo imaging techniques.
Key words: neuro-immune interaction, neuropeptides, skin, dermatitis, bowel, IBD, proinflammatory, antiinflammatory

Co-supervisor: Dr. POZSGAI, Gábor

Among other members of the TRP receptor family, capsaicin-sensitive sensory neurons express Transient Receptor Potential Ankyrin 1 (TRPA1) ion channels. TRPA1 can be activated by several exogenous and endogenous chemical stimuli, such as pungent agents (mustard oil, cinnamaldehyde, allicin) and toxic gases (acrolein, formaldehyde) resulting in the release of inflammatory peptides (SP, CGRP). Hydrogen-sulphide (H2S) is an important gaseous mediator of the human body. In the recent years, there have been several data published, indicating that H2S may be involved in various vascular and inflammatory processes. Moreover, it has also been suggested that H2S may act on capsaicin-sensitive peptidergic neurons. The aim of our investigation is to reveal the interaction of neural and non-neural TRPA1 receptors and H2S in microcirculatory processes, in dermal, intestinal and airway inflammations, as well as in neuropathic states, with the help of in vivo and in vitro experimental methods.

Co-supervisor: Dr. HORVÁTH, Ádám István

TRPA1 and TRPV4 receptors are expressed on capsaicin-sensitive sensory neurons, immune cells and keratinocytes. TRPA1 receptors are activated by pungent agents (mustard oil, cinnamaldehyde), exogenous and endogenous toxic chemicals, as well as inflammatory mediators and noxious cold (<17°C). The activation and sensitization mechanisms and interactions of TRPV4 are less known. Therefore, we aim to analyze their roles and cross-talks in inflammatory and neuropathic pain models with thermo- and mechanonociceptive testing methods using gene-deleted mice pharmacological interventions.

Co-supervisor: Dr. HORVÁTH, Ádám István

Amino-oxidases neutralise the pharmacological effects of exogenous and endogenous biogen amines. However, their reaction products (aldehyde, hydrogen-peroxide, ammonia) are biologically active, potentially toxic compounds. Although the substrate-specificity of these enzymes and their sensitivity to enzyme inhibitors is well-known, their physiological and pathophysiological role is not cleared yet. Therefore, as a continuation of our former experiments, we investigate their function in neuropathic, postoperative and inflammatory pain conditions.

Co-supervisor: Dr. GASZNERNÉ, Dr. Kormos Viktória

Clinical and experimental data indicates that chronic stress increases pain sensitivity, but the underlying mechanisms are largely unknown. The pain perception of mice exposed to chronic restraint stress is assessed with functional tests in our experiments. Neuronal activation caused by stress and pain is examined with immunohistochemistry both in the central and peripheral nervous system. The role of peripheral capsaicin-sensitive sensory neurones is explored with desensitized animals. Investigation of the stress-induced hyperalgesia may contribute to the understanding of stress-related pain syndromes (e.g.: fibromyalgia) and to the identification of new drug targets.

Measurement of the noxious heat threshold is a new concept in the investigation of heat-induced pain, i.e. thermonociception in awake animals. Conventional methods of thermonociception measure the latency (i.e. time) of pain-avoiding (nocifensive) behavioral reactions evoked by a suprathreshold heat stimulus. In contrast, with the recently developed increasing-temperature water bath it is possible to measure the noxious heat threshold of the hind paw or tail in rats or mice by determining the lowest bath temperature that can evoke a nocifensive reaction. This novel equipment has been validated in several experimental models in which heat hyperalgesia manifested itself as a decrease of the noxious heat threshold. Future work aims at investigating other paradigms associated with a drop of heat threshold and revealing their mediators as well as pharmacological modulation including testing of analgesics.

Co-supervisor: Dr. BÖRZSEI, Rita Judit

Computational docking is an essential tool of drug design widely used by pharmaceutical companies. The project will focus on the prediction of structure and energy of drug-target interactions by computational docking. Both capabilities and limitations of the method will be investigated on a set of drug-target systems. The set will be assembled on the basis of common interest of the student and the supervisor.

Co-supervisor: Dr. ZSIDÓ, Balázs Zoltán

Epigenetics plays an important role in the pathomechanisms of various diseases. Modifications of histone proteins of the nucleosome, the “histone code” is fundamental in understanding of diseases with epigenetic background. In this project, we will study the effect of the modifications on structure and interactions of histones focusing on their role in disease pathomechanisms. Structural bioinformatics tools will be applied in our investigations.

Co-supervisor: Dr. BÖRZSEI, Rita Judit

Application of pharmacoinformatics tools is essential in modern drug design. The project will focus on the development of computational tools facilitating efficient discovery of potent drug candidates. The tools work with atomic resolution structures of (protein) targets and calculate the strength of drug-target interactions. Students interested in physical chemistry with programming and/or scripting skills (interest) are good candidates for participating in this project.

Co-supervisor: Dr. ZSIDÓ, Balázs Zoltán

Attacking the assembly of HIV capsid is promising strategy of fighting AIDS. Proteins of the viral capsid are good targets of drug design due to their low mutation rates. In the project, available assembly inhibitors will be collected and their mechanisms will be investigated by computational techniques. Based on the collected information and the uncovered mechanisms, new inhibitors will be also designed.

Co-supervisor: Dr. BÖRZSEI, Rita Judit

Signal transduction is a key to understanding pathomechamisms of various diseases. Signaling pathways are often based on the formation of complexes between protein partners. In many cases, experimental determination of atomic resolution structures of protein complexes (required by drug design) is difficult. In the present project, we will calculate the structure of such complexes using computational tools. We will also study their molecular dynamics to understand their role in signaling and provide starting information for drug development.

Co-supervisor: Dr. ZSIDÓ, Balázs Zoltán

GFR is an essential clinical parameter describing kidney function. The present topic involves a comparative literature survey of the methods of determination of GFR as creatinine clearance. In case we can find available literature and electronic healthcare records, we will apply statistical approaches to evaluate the significance of the state of art methods and will propose probable changes. Likewise, depending on the availability of data we will investigate the connection between physiological parameters (such as blood pressure) and GFR.

Co-supervisor: Dr. ZSIDÓ, Balázs Zoltán

Current drug repositioning possibilities are investigated via generation and evaluation of target-ligand complex structures. During the research work, up-to-date pharmacoinformatic methods are applied.

Co-supervisor: Dr. BÁTAI, István Zoárd

In this topic effects of hydrogen sulfide, sodium polysulfide and dimethyl trisulfide are investigated. Beside classical models of nociception and inflammation, animal modles of neuropathic pain, arthritis and pancreatitis are utilized. Mechanical and heat sensitivity, myeloperoxidase enzyme activity, oedema formation, rate of plasma extravasation as well as activation of corresponding parts of the CNS by immunohistochemistry are detected during the experiments. 
 

Co-supervisor: Dr. ACZÉL, Timea

Orofacial pain and primary headache disorders are among the most debilitating pain conditions. Due to several therapy-resistant patients, the therapy of migraine is far from being optimal, and it is still an unmet medical need. Therefore, understanding the pathophysiological mechanisms is crucial to identify key mediators and determine novel therapeutical targets. Thus, we investigate the role of different potential target molecules in pain models using pharmacological tools (agonists, antagonists) and gene-deficient mice. In our experiments, we investigate different reactions with vascular imaging and behavioural studies, using chemical or electrical activation of the trigeminovascular system.

Co-supervisor: Dr. ACZÉL, Timea

Orofacial pain and primary headache disorders are among the most debilitating pain conditions. Due to several therapy-resistant patients, the therapy of migraine is far from being optimal, and it is still an unmet medical need. Therefore, understanding the pathophysiological mechanisms is crucial to identify key mediators and determine novel therapeutical targets. Thus, we investigate the role of different potential target molecules in pain models using pharmacological tools (agonists, antagonists) and gene-deficient mice. Tissue samples from our experiments are analyzed by qPCR for gene expression and immunohistochemistry for protein level analysis.

Insight into the functional changes of tissues and cells may by examined by visualization of mRNA molecules and their protein products. With the help of ultrasensitive in situ hybridization (RNAscope) technique, it is even possible to detect individual molecules at cellular level. The technique may also be combined with immunohistological methods, so the changes can be examined and quantified both at mRNA and protein level by confocal microscopy even within the same tissue samples or cells.

This approach may help to determine the molecular background of functional or behavioral changes observed in in vivo models for various diseases. A wide range of animal models including mutant mouse lines are available in our lab also.

Ten percent of the population suffers from this neurological disease. It is three times more common in women than in men. Migraine headaches are typically recurrent, throbbing, unilateral, and seizure-like. Nausea, vomiting, photosensitivity may be the accompanying symptoms. In sensitive individuals, certain substances and situations trigger seizures. As migraine attacks deteriorate the quality life considerably, our main goal here is to gain deeper insight into the underlying brain territories to identify new potential therapeutical targets in the brain. The exact pathomechanism of migraine is still not fully understood, but triggering factors include hormonal changes, stress exposure, disturbances of the daily rhythm affecting sleep, and certain weather conditions.

Interestingly, the recruitment of the Edinger-Westphal nucleus (EW) by stress adaptation response, circadian rhythm, and estrus cycle is known. In addition, a number of neurotransmitters are found in EW that are also involved in the pathophysiology of migraine. Gene-deficient animals and in vitro techniques are available for our research, which can be used to describe the functional and neuromorphological changes in various migraine models at both mRNA (RNAscope, PCR) and protein (IHC) level.

TRPA1 is a non-selective cation channel activated by a wide range of irritants, nonxious cold and pro-inflammatory cytokines. Since it is permeable for Ca2+, Na+ and K+, its activation results in membrane depolarization, action potential discharges and neurotransmitter release both centrally and peripherally. It is predominantly expressed in primary sensory neurons and epithelial cells. Trpa1 mRNA expression in adult and developing mouse brain has been poorly investigated. Therefore, the main goals of this study are (i) to map Trpa1 mRNA expression both spatially and temporally on sagittal and coronal sections of developing mouse brain by using the ultrasensitive RNAscope in situ hybridization technology, since currently no specific α-TRPA1 antibody is commercially available; (ii) to co-localize Trpa1-positive regions and stages with specific neuronal markers either performing multiplex RNAscope or RNAscope combined immunostaining procedure depending on the availability of the antibody specific to the neuronal marker of interest.

Co-supervisor: Prof. Dr. HELYES, Zsuzsanna

Endometriosis is a complex estrogen-dependent an inflammatory condition defined as the presence of endometrium-like tissue at ectopic sites. The disease affects around 10-12 % of women of reproductive age, causing chronic pain and infertility. Complex sensory-vascular and immune reactions play a role in its development and progression, but the underlying mechanism and therapy remains to be clarified. Capsaicin-sensitive nerve ending-related cytokines and neuropeptides as well as Transient Receptor Potential Ankyrin 1 (TRPA1) and Vanilloid 1 (TRPV1) receptors are assumed to be involved in endometriosis and consequently chronic pain, but their role is yet unclear. During this thesis, we investigate inflammatory cytokines, chemokines, growth factors, neuropeptides, and nociceptive receptors in human serum and tissue samples as well as in human endometriosis and stromal cell lines.