National Science Centre

The aim of the project is to investigate the influence of increased concentration of indole-3-propionic acid, bacterial metabolite of tryptophan, in intestines and blood on blood pressure and development of hypertension.

Infectious diseases are infection-related complications are one of the leading causes of death in cancer patients. Moreover, microbial resistance to antibiotics as well as increasing evidence of antibiotics-related microbiome disturbance leading to anti-cancer treatment resistance have emerged in recent years as a significant problem from both the medical and the socio-economic perspectives. Therefore, identification and validation of novel targets to reduce the risk of mostly fatal bacterial infections in cancer patients is of far-reaching significance. The aim of this project is to i) investigate the role of immunomodulatory erythrocyte progenitor cells (EPCs) in the progression of plasma cell myeloma (PCM) in mice, ii) to determine the role of EPCs in susceptibility of PCM-bearing mice to bacterial infections, and to iii) validate whether targeting of EPCs immunomodulatory mechanisms improves bacterial infection control in PCM-bearing mice.

The aim of this project is to evaluate clinical usefulness of different TDM protocols in patients after kidney and liver transplantation, which include measurements of C0 and AUC in the whole blood and free TAC C0 in plasma ultrafiltrate. Additionally, the significance of CYP3A5 variant on TAC concentrations will be addressed. The values will be correlated with clinical endpoints such as BPAR and adverse drug effects.

The aim of the project is the assessment of the influence of applying mechanical liver perfusion in hypothermia on the limitation of lesions to the organs collected from donors diagnosed with brain death and the associated improvement in organ function after transplantation.

Self anomalies, i.e. distortions in subjective experience of oneself and the outside world as well as self-awareness, are considered a key feature of psychotic disorders. According to some researchers, it is the self anomalies that underlie the development of psychotic symptoms, both positive and negative. The growing belief in the importance of these experiences for a full understanding of psychosis is also confirmed by the fact that they are included as a diagnostic criterion for schizophrenia in the beta version of the ICD-11 classification. Moreover, studies have shown that self anomalies are present not only among patients diagnosed with psychotic disorders, but also in healthy people with a high frequency of quasipsychotic experiences.

Quasi-psychotic experiences (PLEs) are phenomena that include, inter alia, delusional-like thoughts, or subclinical delusions or hallucinations about which a critical judgment is preserved, and phenomena related to an overly vivid imagination. It has long been postulated that positive psychotic symptoms lie on a continuum where psychotic disorders are at one end, and quasi-psychotic experiences at the other end.

Despite the undoubted importance of self anomaly for the conceptualization of psychosis, little is known about the prevalence of these disorders in the population and the underlying mechanisms. Nelson and his team (2014) proposed that a potential source of self anomaly may be cognitive distortions, i.e. dysfunctional patterns of information processing leading to maladaptive conclusions and emotional dysregulation. According to Nelson, one of the distortions that can contribute to self anomalies are source monitoring deficits. Source monitoring involves, for example, difficulties in distinguishing whether an event really happened, or whether we were just imagining it or someone told us about it. However, Nelson's hypothesis has not been extensively verified empirically so far. Moreover, there are also data suggesting that traumatic experiences may be at the root of self anomalies. Dysfunctional ways of coping with the experience of trauma may cause disturbances in the structure of the self and thus contribute to self anomalies such as loss of boundaries between oneself and the outside world or experiences of depersonalization. The aim of this project will be to verify the model according to which traumatic experiences and cognitive distortions underlie the development of self anomalies.

Prospective studies have shown that self anomalies make it possible to predict the onset of psychosis in a sample of people with a clinical state of very high risk of developing this disease, and thus can be used as an important tool for the early detection of the risk of developing psychotic disorders. However, there are no longitudinal studies that would verify the predictive value of self anomaly for the fluctuation of quasipsychotic symptoms over time and / or the development of psychosis in non-clinical (non-help) groups, but with a high frequency of PLEs.

The objectives of the study include:

1. Determination of the epidemiology of self anomaly in the population of people aged 18-35.

2. Determination of the mechanisms of self anomalies by examining their relationship with cognitive distortions and traumatic life events.

3. Longitudinal examination of self anomalies, i.e. re-evaluation of the respondents after 12 months to check whether the self anomalies predict fluctuations in the frequency of quasi-psychotic experiences and / or the development of psychosis.

The research will be carried out in three stages. In the first stage, screening will be carried out on a population of 6000 people aged 18–35 in order to estimate the prevalence of self anomaly in the non-clinical population (not seeking help) and to identify people at high risk of developing psychosis (high frequency of PLEs) (n = 200). The selected people (n = 200) will be invited to an experimental study (Fish Task, Action Memory Task and Overperceptualization Task) and questionnaires (CECA.Q, IPASE, DACOBS, PQ-16) assessing the occurrence of trauma and a wide spectrum of cognitive distortions. Additionally, with the help of structured interviews (CAARMS and SQUEASE), a comprehensive, multidimensional assessment of psychopathology (including self anomalies) will be carried out. Using the path analysis, the model of relationships between trauma and cognitive distortions and the intensity of self and PLEs anomalies will be tested. In the last stage (follow-up), after 12 months, a clinical reassessment of psychopathology will be carried out, thanks to which it will be possible to test the predictive value of the self anomaly model to predict the increase in PLEs and / or the occurrence of psychotic symptoms.

In addition, the control group (80 people) will also be examined, which will enable the comparison of the mechanisms of self anomalies and the dependencies of the studied variables in people with high and moderate amounts of PLEs.

The result of this project will be to fill the gap in the existing knowledge about the mechanisms of self anomalies. Thanks to the longitudinal study, it will also be possible to gain knowledge about the dynamics of these experiences and their importance in predicting the development of psychosis. The obtained results may supplement the models of therapy for people at high risk of developing psychosis, but also for people suffering from psychotic disorders. Self anomalies in the treatment of these patients have so far been rarely taken into account.

Bacteriophages (phages), are viruses which specifically infect and destroy bacterial cells without adversely affecting eukaryotic cells. One of their very important features is the ability to kill antibiotic- resistant bacteria. In fact, bacteriophages are currently considered one of the most promising alternatives to combat imiltidrug-resistant bacteria. While the interactions of phages and bacterial cells have been studied in great detail, relatively less is known about other effects of this group of viruses.

The main aim of the study is to validate the thioredoxin system as a new therapeutic target in the treatment of B-ALL with the use of cell lines, material isolated from B-ALL patients, as well as with the use of mouse models.

Organic boron compounds play an increasingly important role due to their usefulness in various fields of science. Currently, they are widely used in modern synthesis as convenient and readily available substrates for the preparation of complex organic molecules with specific properties, including drugs or conductive polymers. Currently, more and more hopes are associated with the study of biological properties and the direct application of boron compounds in medicine. An example is the Boron-Neutron Capture Therapy (BNCT) anti-cancer therapy. In recent years, great interest among researchers has aroused in benzoxaboroles - a group of boracyclic compounds, the molecules of which are composed of condensed rings: benzene and the five-membered ring of oxaborole composed of, among others, from boron and oxygen atoms. It has been found that some benzoxaborole derivatives exhibit high antifungal, antibacterial, antiparasitic and anti-inflammatory activity, and at the same time they are not very toxic. Potential applications of these compounds relate to the treatment of important diseases such as African sleeping sickness, malaria and fungal infections. Recently (July 2014), one of these compounds (Tavaborole AN2690, trade name of the preparation Kerydin) has been approved for use in the treatment of onychomycosis. A little later, another compound (Crisaborole, trade name for Eucrisa) was introduced for the treatment of atopic dermatitis. Another boraheterocyclic compound with high antibacterial activity is Vaborbactam - an inhibitor of enzymes that break down carbapenems, "last-chance antibiotics". It has been approved for the treatment of severe, complicated urinary tract infections caused by Enterobacteriaceae. In clinical trials, there are other compounds with a similar chemical structure showing activity against Gram-negative rods, which is another argument for the advisability of further research on this type of substances. This project concerns the synthesis and testing of the properties of selected groups of boracyclic compounds containing a boron atom in one of the rings (additionally fused with an aromatic ring).

An important part of the project concerns the assessment of their antimicrobial activity (killing against bacteria and yeast-like fungi). It should be strongly emphasized that research aimed at developing new classes of biologically active substances with antibacterial and antifungal properties is becoming increasingly important. This is due to, inter alia, from the growing resistance of bacterial strains to currently used antibiotics. It is also planned to investigate the properties of the obtained compounds as inhibitors of enzymes responsible for bacterial resistance to drugs and as inhibitors of membrane pumps that remove substances harmful to bacteria from the cell, including antibiotics. We recently obtained preliminary, promising results on the biological properties of synthesized compounds containing silicon and oxygen atoms in the boracyclic ring. Therefore, it is worth not only continuing but also extending this work, especially in the areas related to medical and bioanalytical chemistry. These studies would also include compounds with a similar structure containing, inter alia, a phosphorus atom in a boracyclic ring.

Glycosomes are organelles characteristic of some unicellular organisms, including the Trypanosoma parasite. Glycosomes are genetically related to peroxisomes found in higher organisms, but in parasites they play a much more important role. It is enough to mention glycolysis, which is the only source of energy in the form of adenosine triphosphate (ATP) for T. brucei, the parasite that causes African coma. Glycolysis is a less important source of energy for the Chagas disease-causing T. cruzi, but this microorganism carries out other important biochemical processes in glycosomes, such as the synthesis of sterol, pyrimidines, and reduction of trypanothio.

Glycosomes are unable to produce their own enzymes for these essential processes, so these proteins must be transported from the cytosol. They are directed to this organelle with the participation of proteins called peroxins (PEX). Of these, PEX14 and PEX5 are the most important. Their combination is believed to allow the enzyme to be transferred across the membrane of the glycosome. Hence, blocking the formation of such a complex can inhibit enzymatic transport and consequently lead to severe negative metabolic effects. It has been proven that the inhibition of the activity of individual glycolytic enzymes by small-molecule organic compounds may result in the death of the parasite cell.

Diminishing the function of all enzymes at once by blocking their import into the target organelle should have at least as severe consequences.

This project aims to obtain new chemical compounds, small-molecule inhibitors that will prevent the PEX14-PEX5 proteins from joining, block the import of enzymatic proteins into the glycosome and, as a result, cause the death of the parasite's cell. So far, only one class of such compounds has been obtained, which in addition had inadequate pharmacological properties, and thus potentially low activity in biological systems. The main goal of the project is therefore to create new classes of inhibitors with at least equal PEX14 binding and protozoal activity, but with better properties such as solubility and pharmacokinetic profile. For this purpose, research methods such as computer-aided design of ligands based on the protein structure, organic synthesis as well as biophysical and cellular assays will be used. The conclusions drawn from the research will not only provide a better understanding of the biochemical processes taking place in glycosomes, but may also lay the groundwork for the design of new, alternative therapeutic strategies for deadly tropical diseases caused by parasites of genus trypanosomes.

Epilepsy is one of the greatest therapeutic challenges in today's neurology. Unfortunately, despite the introduction of newer and newer preparations into treatment, as many as 30% of patients show resistance to pharmacotherapy (the so-called drug-resistant epilepsy). Hence, there is a need for new and alternative therapeutic strategies.

The proposed research corresponds with this direction. In recent years, in cooperation with
Epilepsy Therapy Screening Program (ETPS), we have discovered a series of pyridylacetamide derivatives, novel sodium channel blockers, with extensive activity in animal models of epilepsy (including drug-resistant epilepsy). As a development of this direction, we propose to enrich the in vivo activity profile of one of the most active pyridylacetamides (code name - ADD424042), through its chemical conjugation with another compound found in advanced research preclinical for epilepsy, glycogenesis inhibitor, 2-deoxy-d-glucose (2DG). Such a conjugate should have better anticonvulsant properties than either of the substances separately. This assumption is based on the fact that ADD424042 and 2DG have different mechanisms of action, and their profiles in in vivo studies are complementary (e.g. 2DG is not active in MES and scPTZ models, and is more effective than ADD424042 in drug-resistant kindle convulsions models). Therefore, we assume that a properly designed conjugate will interact with the molecular targets of both parent compounds, and that its pharmacological profile in in vivo tests will be additive or even amplified.

2DG is known to penetrate the brain in an active manner dependent on GLUT-type transporters. Expression of these
transporters is higher in areas where there is a high demand for energy (incl. areas of the brain affected by epileptic discharges), which suggests that the relationship will be selectively delivered to neurons with disturbed excitability and that it will stay in these cells trapped after phosphorylation by hexokinase. This may be relevant to ADD424042's effects as
a sodium channel modulator as the compound is likely to act intracellularly. The first stage of the project will be to obtain a properly designed conjugate. According to the SAR data of the ADD424042 analogs, the substituents on the amide nitrogen are tolerated. On the other hand, literature reports show that the acylated derivatives of 2-amino-2DG
are subject to active transport. The essence of the synthesis is the coupling of ADD424042 with 2-DG. For this, you will need to receive key ester 1 followed by its aminolysis with a linker, b-alanine tert-butyl ester. This process, catalyzed by the strong guanidine base, is chemoselective towards the methyl esters. We know from previous studies that aternative hydrolysis of compound 2 is not possible because it is simultaneously decoxylated. The next planned stage is deprotection
derivative 2 and conjugation of the released carboxyl group with the amine derivative of 2DG. The next step will be to determine the inhibitory activity of the glycolytic enzymes: isomerase glucosephate and hexokinase (test kits are commercially available). Both of these enzymes are inhibited by 2DG, while 2DG and 2-acylamino-2DG are known inhibitors heskokinases. The basic ADME profile will be determined: microsomal and plasma stability, plasma protein binding, logD, biological membrane permeability (Caco-2), susceptibility to P-glycoprotein-mediated release, inhibition of cytochrome P450 and hERG channel. Tests are required to submit an ETSP for the compound to be qualified for in vivo testing. After completing the project, the ability to modulate sodium currents will be tested, characterizing ADD424042. The described tests will help to determine the usefulness of the planned ones conjugates as compounds with in vivo activity in animal models of epilepsy; and examination under the ETSP. If a proof-of-concept is obtained, another one will be submitted as grant application, presenting a plan for optimization and further research on 2DG conjugates.