RP8 Translational Neuroscience – Running Grants and Projects

NATIONAL PROJECTS EXCEPT OPERATIONAL PROGRAMMES

The Czech Science Foundation

Novel Model of Psychotic Relapses and Their Influence on Cognitive Deterioration, Structural and Functional Brain Changes (18-09296S)
Investigator: RNDr. Karel Valeš, Ph.D.
Principle investigator: NIMH
Co-investigators/Partners: Institute of Physiology of the CAS (prof. MUDr. Pavel Mareš, DrSc.); Charles University Prague, 3rd Medical Faculty (prof. MUDr. Romana Šlamberová, Ph.D.)
Duration: 1.1.2018–31.12.2020
Total budget: 12 644 000 CZK
Total budget NIMH: 6 695 000 CZK
Abstract: There is a contemporary consensus that there is further worsening of symptoms with each relaps in schizophrenia. These symptoms include pathophysiological changes and neurodegeneration, which may ultimately leads to gray matter shrinkage in the final stages of schizophrenia. This project aims at studying this phenomenon and at designing an innovative animal model. Design and evaluation of the valid animal model of schizophrenia progression is important for studying the neurobiological mechanism as well as for suggesting potential pharmacological approaches to its treatment. Recently designed model is based on the early immune stimulation and repeated injection of drugs causing psychosis-like behavior in animals. Thus, important output of this study is to facilitate testing of the europrotective effect of the substances with antipsychotic properties on the progression of the disease and selecting the most appropriate ones.

Czech Health Research Council

Novel Neuroprotective Compounds Based on NMDA Receptor Antagonism and Cholinergic Stimulation (20-12047S)
Investigator: RNDr. Karel Valeš, Ph.D.
Principle investigator: University Hospital hradec Králové (PharmDr. Ondřej Soukup, Ph.D.)
Co-investigators/Partners: NIMH; Institute of Experimental Medicine CAS (Mgr. Martin Horák Ph.D.)
Duration: 1.1.2020–31.12.2022
Total budget: 14 980 000 CZK
Total budget NIMH: 4 996 000 CZK
Abstract: In this project, we would like to follow-up the proof-of-concept project no. 16-08554S, focused on the dually acting tacrine derivatives, in the preclinically-oriented project focused on 7- MEOTA and its derivatives, where we would like to investigate and understand the mechanism of interaction of such compounds with the open-channel of the NMDA receptor. We will use in vitro data of native and specifically mutated NMDA receptors, molecular docking approaches and quantitative structure-activity relationship (QSAR) approach to describe such interaction. Such investigation is giving us also a tool for designing even more effective neuroprotectants. Therefore, the candidates with the most promising pre-clinical potential showing suitable NMDA receptor inhibitory properties while preserving anti-acetylcholinesterase activity will be subjected to thorough preclinical in vivo testing in order to evaluate and verify the real neuroprotective and pro-cognitive value rising from the dual character of such compounds.

Role of Neuroactive Steroids in Mechnanism of Action of Clozapine (NU20-04-00389)
Investigator: RNDr. Karel Valeš, Ph.D.
Principle investigator: NIMH
Project partners: Institute of Endocrinology, Insitiute of Physiology CAS
Duration: 1.5.2020–31.12.2023
Total budget: 18 949 000 Kč
Total budget NIMH: 8 358 000 CZK
Abstract: The aim of the project is to study the alterations in steroidome after clozapine treatment in patients suffering from schizophrenia. Specifically, we will focus on the correlation between changes in the levels of neuroactive steroids and the reduction of positive and negative symptoms of schizophrenia following clozapine administration. Next aim is to demonstrate whether the application of clozapine induces qualitatively different changes in neurosteroid levels in the hippocampus, prefrontal cortex, and striatum of laboratory rats compared to haloperidol, risperidone and olanzapine.
The last but not least aim is to demonstrate that the adjuvant co-administration of 3a5ß substituted pregnanes with olanzapine, risperidone and haloperidol leads to a reduction of cognitive deficit in the animal model of schizophrenia compared to the antipsychotics alone. Research results will have a clear impact on the clinical practice in two fields. At first is in the field of diagnosing the prediction of therapeutic response in patients suffering from schizophrenia and the selection of patients to benefit from clozapine therapy. The second area will be the possibility of subsequent development of adjuvant pharmacotherapy of psychotic diseases using 3αC substituted pregnane derivatives. In our previous projects, we have demonstrated the role of neurosteroids in schizophrenia in both the animal model and clinical research. Furthermore, we demonstrated the effect of pragnanolone derivatives in the animal model of schizophrenia. A number of studies suggest that different levels of neurosteroids may explain differences in the therapeutic response. Antipsychotics can normalize altered levels of neurosteroids, but they also have their own antipsychotic potential and can be used as adjuvant therapy to affect the negative and cognitive symptoms of schizophrenia.
It is in this direction that our research will go. In the preclinical part, we will study changes in neurosteroid levels in the CNS in the animal model of schizophrenia in response to the application of typical and atypical antipsychotics. Consequently, adjuvant therapy with pregnane derivatives will study the potential for an increase in the antipsychotic effect of antipsychotics. In the clinical part, we will focus on steroid changes in the blood of schizophrenia patients who can predict response to clozapine.

Dually Acting Cognitive Enhancers for Palliative Treatment of Alzheimer´s Disease (NU20-08-00296)
Investigator: RNDr. Karel Valeš, Ph.D.
Principle investigator: Fakultní nemocnice Hradec Králové
Project partners: NIMH, Ústav experimentální medicíny AV ČR
Duration: 1.5.2020–31.12.2023
Total budget: 16 691 000 Kč
Total budget NIMH: 5 701 000 Kč
Abstract: Aim of the project is to investigate effect of NMDAR antagonists on the glutamatergic system and potential benefits of dually acting compounds (targeting both the ChE and NMDAR) on cognition and possible protection from neurodegeneration associated with the Alzheimer disease. The ultimate goal is to develop novel clinical candidates for the palliative treatment of AD. The milestones of this study are (without time designation): • Examine effects of memantine on protein expressions for the excitatory synapse complex and NMDARs from a collection of human brain samples. • Examine correlation of behavioral and cognition benefits of selected compounds (memantine, THA, 7-MEOTA, 7-FEOTA) to alterations in the total protein expression including the excitatory synapse complex and the NMDARs using the GMO AD animal model. • Synthesize newly designed compounds and characterize their potential therapeutic values. • Determine the benefits underlying the interaction of novel compounds with the NMDARs while preserving, preferably non-selective, anti-ChE aktivity. • Select at least one candidate molecule for in vivo studies. • Evaluate pharmacodynamics and pharmacokinetic profiles of the candidate(s) with in vivo efficacy and their toxicity in vivo. Alzheimer´s disease (AD) and other neurodegenerative diseases leading to dementia represent a serious health, social and economic problem symptomatologically manifesting as cognitive disorder and dementia. Currently available treatment of the cognitive decline is based on the administration of acetylcholinesterase inhibitors (AChEI) and/or N-methyl-D-aspartate receptor (NMDAR) antagonist memantine. Thus, to potentiate cholinergic transmission and simultaneously block the excessive Ca2+ excitotoxicity is supposed to be a promising strategy to, at least, delay the progression of the disease and enhance cognition. Motivated by previous findings, we will investigate the effect on memantine on NDMAR expression using human samples and subsequently potential benefits of dually acting compounds as the cognitive enhancers and neuroprotectants against neurogeneration. We will perform in vitro and in vivo drug development process including the GMO animals in order to deliver dually acting clinical candidates.

The Technology Agency of The Czech Republic

Application of research methods to design a system of services for psychedelic users (TJ02000156) Investigator: Mgr. Rita Kočárová
Principle investigator: NIMH
Duration: 27.3.2019–31.1.2021
Total budget NIMH: 2 178 482 CZK
Abstract: The main objective of the project is to explore the use of psychedelic substances in the Czech Republic using research methods and to reflect the results in the development of strategic documents on drug policy and services system at national and regional level. Other objectives are to analyze the potential impact of these substances on mental health and quality of life for users, identify risks related to their use and user needs, analyze motivation to use, and identify risky patterns of use. Based on the data and results obtained, it will be possible to design a missing service system and update existing services to meet the needs of users of these substances within the harm-reduction philosophy.

BrainTech: Innovative Technologies for Psychiatry and Clinical Neuroscience (BrainTech) (TP01010062)
Investigator: RNDr. Karel Valeš, Ph.D.
Principle investigator: NIMH
Dutarion: 1.1.2020–31.12.2022
Total budget NIMH: 14 970 000 Kč
Abstract: The BrainTech project aims to a comprehensive system to support individual projects proof-ofconcepts in the field of psychiatry, aging and clinical neuroscience. Through the selection of partial projects in the fields of digital health, telemedicine and drug research and development, projects with commercial potential will be developed and the transfer of results of research and development to the application sphere, both in the Czech Republic and abroad, will accelerate.

Ministry of Industry and Trade of The Czech Republic

Biotechnology research into microbiological spectrum changes to improve cognitive functions, depression and other neuropsychiatric disorders, particularly in the aging population – CleverAge Biota (FV40032)
Investigator: RNDr. Karel Valeš, Ph.D.
Principle investigator: C2P s.r.o. (MUDr. Róbert Hromádka)
Duration: 1.5.2019–31.12.2022
Total budget: 28 199 996 CZK
Total budget NIMH: 13 822 996 CZK
Abstract: The goal of the project is to developed probiotic functional foods intended for the elderly population able to modify the changes in the composition of the intestinal microbiota typically occurring in the elderly, ie normalization of the physiological axis of the brain-intestinal-intestinal microbiota, which according to current scientific knowledge affects the activity of the nervous system. As a result, cognitive functions will be improved and the quality of life improved.

OPERATIONAL PROGRAMMES

OP Research, Development and Education 

Centre for Technology and Knowledge Transfer NIMH (CZ.02.2.69/0.0/0.0/16 014/0000656)
Investigators: RNDr. Karel Valeš, Ph.D., Ing. Šimon Skovajsa
Principle investigator: NIMH
Duration: 1.7.2016–30.6.2020
Total budget NIMH: 16 140 949 Kč
Abstract: The Project sets out as its objective setting up and development of a comprehensive system for transferring knowledge into practice in the National Institute for Mental Health, being subsidized from the OP VaVpl PO II Operational Program with the sum of CZK 971 million, by accelerating transfer of the research & development outcomes into application spheres both in the Czech Republic and abroad, and to help in identifying the research & development outcomes and in project development with commercial potentials in the fields of psychiatry, psychology, and neurobiology.

PharmaBrain (CZ.02.1.01/0.0/0.0/16_025/0007444)
Investigators: RNDr. Karel Valeš, Ph.D., Ing. Šimon Skovajsa
Principle investigator: NIMH
Co-investigator-Partner: Institute of Physioloogy CAS; Charles University, 3rd Medical Faculty; University of Hradec Králové
Duration: 1.1.2018–31.12.2022
Total budget: 148 262 697 CZK
Total budget NIMH: 78 821 389 CZK
Abstract: The present project focuses on the research of a glutamatergic neurotransmitter system, which under physiological conditions controls a whole range of processes in the brain and participates in the management of normal brain development. At the same time, however, its dysfunction plays a significant
role in many neuropsychiatric disorders. The project focuses on its role in both clinical practice and experimental models. This direction of research has a long-standing tradition and a high reputation at an international level in participating workplaces.

OP Enterprise and Innovation for Competetiveness

Identification of drugs and other substances in the aquatic ecosystem – DrugsLab  (CZ.01.1.02/0.0/0.0/17_107/0012547)
Investigator: RNDr. Karel Valeš, Ph.D.
Principle investigator:: E&H services a.s.
Co-investigator/Partnet: NIMH
Duration: 1.7.2018–31.10.2020
Total budget: 16 538 653 CZK
Total budget NIMH: 4 059 126 CZK
Abstract: The project focuses on methodologies for verification of the use of passive samplers for the determination of biologically active substances - addictive substances, pharmaceuticals and other similar compounds in the aquatic ecosystems, at various places in the watercourses. Also included in the passive sampler system are SPRi chips that allow genotoxicity to be determined. The resulting methods of modification of passive samplers, sampling methodology, analytical techniques and advanced information analysis using robust results evaluation methods will be developed both in terms of environmental protection and in terms of abuse and illegal consumption of these substances. The result of the project is not only a functional methodology for detection of these substances, but also testing the possibilities and effectiveness of technology for removing substances of interest from various matrices, which is one of the key areas that the authors of the project have been dealing with for a long time. The developed methodologies will be tested in watercourses at sites expected to occur, such as selected wastewater treatment plants or hospitals. The techniques will be ready for immediate use on suspicion of the presence of these substances in the wastewater, whatever the source member.

Development of DNA-biochips for rational prescription of Psychopharmaceuticals (CZ.01.1.02/0.0/0.0/17_107/0012433)
Investigator: RNDr. Karel Valeš, Ph.D.
Principle investigator: ESSENCE LINE, s.r.o.
Co-investigator/Partner: NIMH
Durtion: 1.1.2018–31.10.2020
Total budget: 11 073 961 CZK
Total budget NIMH: 2 569 868 CTK
Abstract: The aim of the project is to develop a new DNA-biochip for the rationalized prescription of psychopharmaceuticals for patients with psychiatric illness and thereby bring benefits not only to the patient, but to reduce the costs of health insurance companies. The benefit of the project will be a safer and more effective prescription of psychopharmaceuticals, which will lead to more successful pharmacotherapy, increase patient comfort in the form of positive therapy and reduce the cost of inefficiently applied psychopharmaceuticals and negative effects on the patient.