Specific serotonin-dopamin modulators and their potential in the model of induced psychosis
Provider:
Czech Science Foundation
Investigator:
Ondrej Soukup, Jan Korabecny
Abstract:
Current pharmacotherapy of schizophrenia is based on targeted alternations mainly of serotoninergic and dopaminergic system by the second-generation antipsychotics. Besides classic antagonism or partial agoni on dopamine D2receptors, its seems therapeutically beneficial to affect 5-HT3 receptors as well. Current antipsychotics do not show a significant effect on 5-HT3R (with the exception of clozapine), whose antagonization improves, based on research outcomes, sensorial resistance, cognitive impairment, and negative symptoms of schizophrenia. On the basis of augmentation effect of setrons we have therefore proposed and optimized a model (structure) of antipsychotics for animal testing, which could exert partial agonism on D2R, as well as antagonism on 5-HT3R.
We will validate the proposed design in vitro and by the animal model of psychosis also for a tentative clinical use in future. Beside the antipsychotic effect, which should be at ideally comparable to that of clozapine, we believe that the novel model will exert lower incidence of side effects.
Project duration:
1-January-2019–31-December-2021
The influence of experimental gastorintestinal injury and inflammation of pharmacokinetics of Alzheimer´s disease drugs
Provider:
Czech Science Foundation
Investigator:
Jan Bures, Jana Zdarova Karasova
Abstract:
To date there are no information on alteration of pharmacokinetics profile of drugs used in Alzheimer disease (AD) if patients suffer from gastrointestinal dysfunction (due to ischaemia, drug injury and/or inflammatory bowel disease). Such an alteration could be limiting for effective pharmacotherapy of AD. The goal of this project is to determine the significance of capsule enteroscopy to set absorption window of currently available AD drugs and new compound K1065 (a hybrid molecule of tacrine and trolox) in experimental pigs (in health and experimental gastrointestinal injury induced by dextran-sodium sulphate or indomethacin). The second objective is to determine the impact of currently available AD drugs and new compound K1065 on gastric myoelectric activity (as a functional basis for possible gastrointestinal side effects of these drugs). The other aim is in vivo evaluation of pharmacokinetic and anti-inflammatory properties of newly designed compound K1065 in the gastrointestinal tract.
The aim of this project is to set absorption window for pharmacokinetics and bioavailability of currently available AD drugs and new compound K1065 (a hybrid molecule of tacrine and trolox) in experimental pigs and to determine their impact on gastric myoelectric activity.
Project duration:
1-January-2018–31-December-2020
Development of novel radiotrotective agents based on small molecule inhibitors
Provider:
Czech Science Foundation
Investigator:
Jan Marek, Zuzana Sinkorova, Martina Rezacova
Abstract:
Radiotherapy is a very important modality for treating cancer. Its therapeutic potential is however limited by normal tissue damage, which leads to a wide range of symptoms (impeding quality of life of oncologic patients), prevents delivery of intended dose and reduces the tumor-eradicating effect of the therapy. Both acute and chronic radiotoxicity have been associated with cell death. Whereas multiple cell death pathways are executed in cancer cells after irradiation, in radiosensitive tissues such as bone marrow or gastrointestinal tract, the cell death is dominantly mediated via apoptosis. Since a pro-apoptotic protein PUMA plays a key role in this process, its inhibition increases resistance against radiation. Inhibitors of PUMA seem therefore very promising in selective modulation of normal tissue damage durin radiotherapy. Their clinical utilization could be very wide due to PUMA involvement in pathogenesis of myocardial reperfusion injury and neurodegenerative diseases.
Project duration:
1-January-2017–31-December-2019
Novel therapeutic approaches in narcolepsy
Provider:
Czech Science Foundation
Investigator:
Jan Korabecny, Stepan Kubik
Abstract:
Narcolepsy is a condition of orexin deficiency hence, replacement therapy using orexin receptoragonists could be valuable for its treatment. Indications that treatment of narcolepsy with orexinagonists would be effective came from a study demonstrating that chronic overproduction oforexin peptides from an ectopically expressed transgene prevented the development of anarcolepsy syndrome in orexin neuron-ablated mice. Orexin supplementation seemed to be a hopeful way however, a problem with its administration arose as the only effective route is intracerebroventricularly. Therefore, development of small-molecule orexin agonists, able to penetrate BBB, may represent a promising way in treatment of narcolepsy. Additionally, no non-peptide orexin agonist has yet been reported. Pursuant to preliminary screening, 10 potential drug candidates acting as ligands for orexin receptors have been selected. These will be synthesized and in vitro evaluated. The best 4 compounds with desirable biological properties will be forwarded to in vivo studies.
Project duration:
1-January-2017–31-December-2019
Mechanisms of IFNgamma-induced cellular senescence and phenotypic plasticity
Provider:
Czech Science Foundation
Investigator:
Zdenek Hodny, Sona Hubackova, Vojtech Tambor
Abstract:
Senescent cells as non-dividing cells represent a primary tumorigenesis barrier, on the other hand they participate in organism aging and carcinogenesis by production of inflammatory cytokines. Immune system plays a dual role in these processes. Besides clearance of senescent cells from organism it provokes senescence via action of several cytokines. The goal of the study is to highlight molecular mechanisms behind development of senescence induced by interferon gamma (IFNgamma) and transforming growth factor beta (TGFbeta), two cytostatic cytokines principally involved in cancer immune surveillance. We aim to decipher the regulation of key genes involved in growth-suppressing effects of both cytokines, how this control is lost in cancer cells and to characterize phenotypic changes including energy metabolism associated with resistance of these cancer cells to IFNgamma and TGFbeta. We believe this proposal will bring new knowledge about control of cell growth by immune system and mechanisms of escape of tumor cells from immune response mediated by IFNgamma and TGFbeta.
The aim of this project is to characterize cytostatic effects of IFNgamma and TGFbeta with focus on changes in mitochondrial oxidative metabolism and to elucidate phenotypic changes of tumor cells accompanying establishment of resistance to interferon gamma and TGFbeta.
Project duration:
1-January-2017–31-December-2019
Investment evaluation of medical device development
Provider:
Czech Science Foundation
Investigator:
Jan Honegr, Petra Maresova, Martin Augustynek
Abstract:
The aim of the research is to express economic aspects of medical device development. Reasons for solving this problem are limited financial resources of developed countries’ governments, a growing number of patients who live longer due to high quality health care, and governments’ effort to invest in science and research efficiently. The main objective of this project is therefore to create a model capable of describing the potential of investments in medical device development. On its basis it will be possible to optimize processes related to medical device development and market penetration. In order to achieve this objective a review of existing medical device development models will be followed by proposing a new model, which will be discussed with medical device experts from universities, R&D centres, and from companies producing and selling medical devices. The model will be developed for various categories of medical devices. It will lead to creating methodical approaches – supplemented with case studies – to measuring the effectiveness of medical device development.
Project duration:
1-January-2017–31-December-2019
Novel hybrid compounds in the cognitive decline caused by neurodegeneration
Provider:
Czech Science Foundation
Investigator:
Mgr. Martin Horak, Ph.D., PharmDr. Ondrej Soukup, Ph.D., RNDr. Jan Ricny, Ph.D.
Abstract:
This project follows-up with ending 5-year project focused on hybrid compounds. The goal of the project is to characterize predicted NMDA receptor interaction of novel compounds, verified the selected candidate in cognitive decline model in vivo and thus validate the dual approach for
such treatment.
Project duration:
1-January-2016–31-December-2018
Plasmonic nanoparticles for theranostics with tunable optothermal properties
Provider:
Czech Science Foundation
Investigator:
prof. Ing. Kamil Kuca, Ph.D., MUDr. Jiri Bartek, CSc., Dr.h.c.
Abstract:
Principal objective is to developed non-toxic gold nanoparticles optothermally tuned "on demand" for specific areas of their application in theranostics and biomedicinal imaging. Surfaces of the gold nanorods and gold nanodumb-bells will be modified with de novo synthesized ligands.
Project duration:
1-January-2016–31-December-2018
