A) The most common public health problems of today are neurodegenerative diseases, inflammatory gastrointestinal and cardiovascular diseases, the underlying patho-mechanism is not exactly known. The therapeutic palette is incomplete, the available drugs are often only suitable for alleviating the symptoms of diseases. A better understanding of the mechanisms underlying pathological processes is essential for the development and proper application of therapeutic solutions. This is why our project examines the mechanisms of processes involving cell damage in various conditions and the role and modulation potential of tryptophan metabolism in neurodegenerative, inflammatory and cardiological processes. Our project focuses on the kinurenin system with a multidisciplinary approach, therefore the translational value of the results obtained, the possibility of applying it in later medicine can be outstanding. B) The patho-mechanism of neurodegenerative processes may vary in terms of different diseases, but some aspects of pathological processes overlap. The aim of our studies is to identify the mechanisms of basic processes that can be the basis of neurodegeneration as a general phenomenon. Details of degenerative processes related to patho-mechanism of motoneuron diseases are planned to be investigated by spontaneous, age-dependent motoneuron damage, genetically modified mouse strains and acute lesion animal model. We will study motoneurone and axon degeneration of different strains with protein and gene expression analyses indicating morphological and cellular changes, which will be complemented later by human peripheral nerve samples. In induced models, the mechanisms of signalisation of neurons and non-neural cells (mainly microglias) and the involvement of neuromuscular synapses are mapped. Microglys are involved in controlling the balance of neurodegeneration and neuroregeneration by modulating inflammatory processes, which can be monitored by the isolation of microglia populations and the physiological influence of their cytoskeleton. We will characterise the effect of certain inflammatory and inhibitors on the reorganisation of cytoskeletone, the regulation of inflammation-linked genes, analyse the affected intracellular signal pathways. In the central nervous system, we also want to examine the degenerative changes caused by chronic convulsions, a process that can be modelled in mice. After a single administration of a substance, chronic convulsions occur, resulting in hypocampus degeneration months later, with changes in the expression levels of certain glutamate receptor subunits. A morphological and neurochemical examination of the formation and course of neurodegeneration is carried out, in particular with regard to the glutamatergic system. Changes in the expression of the TRPV1 receptor and glucosylceramide synthase, which are involved in the selective neurotoxicity of capsaicin, will be investigated by the latest molecular biological procedures. In addition, the involvement of membrane lipid rafts and their ganglioside components will be studied in the expression of receptors involved in neurodegeneration and nociception. Induction of chaperon proteins is an important new therapeutic option for protein folding disorders affected by patho-mechanism of neurodegenerative diseases. In our studies, we look for chaperone inducing compounds and examine their inducing effects. We optimise their structure and then plan their synthesis, in vitro screening and testing in the blood-brain barrier model, two selected compounds will be tested in the Alzheimer’s model. We will also examine the epigenetic aspect of Huntington’s transcriptal regulation. The role of posttranslation modification of histone proteins and the reorganisation of nucleosomes in the disease is studied. In different animal models, we identify histone methylation modifications, determine the genome regions concerned, changes. Tryptophan metabolism produces a large number of compounds, the role of which has been associated with many diseases. Thus, the kinurenine pathway is the source of molecules that are a potential drug development target, among which the focus of our research is quinurenic acid (KYNA) as a glutamatergic modulator. This requires on the one hand the development of analogue compounds and effective methods of administration and a detailed preclinical study of these methods and, on the other hand, detailed knowledge of metabolism and modulation possibilities. 1. Preparative and analytical chemistry researches of previously produced KYNA analogues have proven to be neuroprotective and immunomodulatory, but these compounds can be considered prodrugs. In the synthesis of newer analogues, we plan to incorporate molecule fragments that themselves show potential pharmacological activity. The sieve