Student Researchers' Society Topics

Chronic pancreatitis is a progressive inflammatory disease leading to irreversible morphological changes and impairment of both exocrine and endocrine functions. Genetics plays an important role in the pathogenesis of chronic pancreatitis, especially in children. Over the past 20 years the role of genetic factors in the etiology of chronic pancreatitis has been extensively studied and a mechanistic model in which premature trypsinogen activation plays a central pathogenic role has been established. More recently, an alternative pathomechanism unrelated to accelerated intrapancreatic trypsinogen activation has been revealed, in which mutation-induced misfolding and consequent ER stress lead to acinar cell damage and pancreatitis. Using animal models of genetically determined chronic pancreatitis we aim to study both pathomechanisms, the trypsin-dependent and the ER stress related pathways in vivo. Moreover, we also focus on the identification of new genetic risk factors in chronic pancreatitis using candidate gene association studies.

Our laboratory was recently established as part of the “Center for Pancreas Disorders” within the Institute for Translational Medicine of the University of Pécs. In the center the students will have the opportunity to master different techniques used in molecular genetics (DNA/RNA isolation, PCR, RT-PCR, Sanger sequencing, mutagenesis, Western blot), biochemistry (affinity chromatography, enzyme activity measurements), cell culture and mouse model experiments.

The students also will have the opportunity to perform some of the experiments in the laboratory of Professor Miklos Sahin-Toth (Boston University), who is a world-renowned researcher in the field of chronic pancreatitis focusing on the genetic background of the disease. Professor Sahin-Toth has a dual role in the projects; he is the director of the Center for Pancreas Disorders at the University of Pécs and he will also serve as an international collaborator.

Co-supervisor: Dr. SZAKÁCS, Zsolt

Cystic fibrosis (CF) is caused by a loss of function mutation in the CFTR chloride channel (most commonly deltaF508), which causes abnormalities in the function of the external glands. It is a complex disorder that is mainly associated with severe respiratory and digestive symptoms and usually affects the pancreas as well. Pancreatic parenchymal damage may occur early in life, even in utero, leading to the development of cystic fibrosis-related diabetes (CFRD). The disease, in addition to other rare causes of diabetes, is classified as type 3 diabetes mellitus.

In this topic, we will perform a meta-analysis to investigate methods used to diagnose CFRD. The purpose of the diagnostic test accuracy meta-analysis is to compare different modalities to each other, thereby ranking them. According to current guidelines, the gold standard diagnostic test is the oral glucose tolerance test (OGTT), but several other modalities are available (e.g., continuous glucose monitoring, fasting blood glucose levels and haemoglobin A1C). Our results can contribute to the selection of the best (and most cost-effective) diagnostic option.

Co-supervisor: Prof. Dr. MOLNÁR, Lajos Zsolt

The severe form of acute pancreatitis is similar in the aspect of pathophysiology and course of disease to septic shock. Both clinical conditions are associated with high mortality. Since the incidence of the severe cases of acute pancreatitis is rare (about 10% of all acute pancreatitis cases), there is only limited information about the course of disease, diagnostics and therapy. The aim of our study group is to establish an extensive research program to study patients who require intensive or subintensive care. In addition to retrospective, prospective and observational studies we are also planning prospective randomized controlled trials. One of our main goals is to expand our knowledge on extracorporal cytokine adsorption therapy, therefore we are initiating multicenter clinical trials on the cytokine adsorption therapy in patients with septic shock and with severe acute pancreatitis.

World Health Organization (WHO) announced the coronavirus disease 2019 (COVID-2019) outbreak pandemic in the morning 12th of March, 2020. As often seen regarding other epidemics, most cases can be asymptomatic or develop only mild symptoms and remain undiagnosed. Therefore, it is hard to estimate the true incidence and the disease outcomes precisely. Nevertheless, it must be noted that we lack evidence-based targeted pharmacological therapy for prevention and treatment alike. The aims of this scientific project are to understand i) the onset, ii) epidemiology, iii) diagnosis, iv) clinical course, v) treatment, vi) therapy and vii) complications of SARS-CoV-2 infection, in addition to investigate the biomarkers and genetic background of this disease.

Age-related regulatory alterations may be assumed in the background of middle-aged obesity and aging anorexia since they also appear in other mammals. Our previous studies described such regulatory alterations of the central catabolic melanocortin system: a weak catabolic responsiveness to alpha-melanocyte stimulating hormone in middle-aged and a strong one in old age-groups. Corticotropin releasing factor (CRF) and urocortins are important catabolic peptide mediators downstream to the melanocortins. Their effects are mediated by CRF1 and CRF2 receptors. In the PhD program we aim to investigate the age- and nutritional state-associated alterations in the central corticotropin system (and those of its receptors). Animal experiments will carried out in different age-groups (from juvenile to old) of laboratory rodents. Regarding nutritional state, we establish ad libitum fed, diet-induced obese and calorie-restricted groups withing the age-groups. During the analysis of central acute and chronic corticotropin responsiveness, food intake is to be recorded in an automated FeedScale system, circadian rhythm of core temperature, heart rate, spontaneous locomotor activity in a biotelemetric system (MiniMitter, Respironics). These measurements will be complemented by the registration of oxygen consumption, core and tail skin temperature (the latter indicates heat loss) in an Oxymax system (Columbus) for indirect calorimetry.
 

Co-supervisor: Dr. GARAMINÉ PÁKAI, Eszter

Whole-body inflammation (e.g., sepsis) is currently the 10th most common cause of death in the world, with roughly 1,400 victims per day. In Hungary, approx. 9,000 patients are treated with sepsis in intensive care units with a 30-60% fatal outcome. Systemic inflammation is closely related to changes in body temperature, which are included in its clinical diagnosis. The majority of patients have a fever, but a significant proportion have a lower than normal body temperature (hypothermia). Successful intensive care of systemic inflammation and reduction of mortality are essential to explore the fundamentals of the physiological and pathophysiological mechanisms involved in that fact, but these are currently the subject of research.

Co-supervisors: Eszter Pákai Garaminé, PhD, research fellow

Based on previous studies the capsaicin receptor (recently known as TRPV1 channel) plays an important role in the maintenance of normal body temperature and body mass. By utilizing rats with functionally impaired TRPV1 channels (capsaicin desensitized), we can model the effects of the lack of TRPV1 in vivo. We want to investigate how the lack of TRPV1 influences the age-related changes of energy balance with measuring the changes of body temperature, body mass and the changes of the effects of central and peripheral an/orexigenic substances in systemically and intra-abdominally desensitized rats as a function of age.

Neuropeptides released from capsaicin-sensitive nerve endings play an important role in inflammatory processes. It is also known that capsaicin desensitization – through not yet clarified mechanisms – influences the development of bacterial lipopolysaccharide (LPS)-induced fever. We want to investigate the role of capsaicin-sensitive nerve ending derived neuropeptides (e.g., substance P, PACAP) and of their receptors in the development of LPS-induced body temperature response, also, to study their effects on the activation of thermoeffectors (heat production, heat conservation) that are recruited in the temperature response.

Fever, hypothermia as well as obesity and cachexia are results of the dysregulation of energy balance. In our research, we plan to study, which mechanisms play a role in the development of energy imbalance. We assume that ion channels (formerly known as the capsaicin receptor, recently TRPV1), which can be activated by capsaicin, the pungent ingredient of hot peppers, furthermore, age-related changes in the effects of certain (anabolic and catabolic) molecules on food intake and on metabolism possess an outstanding role in these mechanisms. Based on the above, we plan to clarify the role of TRPV1 and other TRP channels in the regulation of body temperature and of body mass with special focus on the age-related changes in their function.