RP1 Experimental Neurobiology – Running Grants and Projects

NATIONAL PROJECTS EXCEPT OPERATIONAL PROGRAMMES

The Czech Science Foundation

Electromagnetic Models of Animal Brains (18-16218S)
Investigator: MUDr. Tomáš Páleníček, Ph.D.
Principle investigator: Brno University of Technology (prof. Dr. Ing. Zbyněk Raida)
Co-investigator/Partner: NIMH
Duration: 1.1.2018–31.12.2020
Total budget: 7 240 000 CZK
Total budget NIMH: 3 811 000 CZK
Abstract: The project is focused on the fundamental research of robust methods for the identification of source currents in brains of animals. Methods are unique in combination of quasi-static and full-wave approaches to numerical modeling, exploitation of 3D printing and agar gelatins for the creation of physical models. Created models allow a reliable calibration of inverse solvers which determine magnitude and orientation of source currents from potentials measured on the surface of a brain. Knowledge of source currents is important for neurological research.

Specific Serotonin-dopamin Modulators and Their Potential in the Model of Induced Psychosis
(19-11332S)
Investigator: PharmDr. Jan Korábečný, Ph.D.
Principle investigator: University Hospital Hradec Králové (PharmDr. Ondřej Soukup, Ph.D.)
Co-investigator/Partner: NIMH
Duration: 1.1.2019–31.12.2021
Total budget: 8 872 000 CZK
Total Budget NIMH: 4 973000 CZK
Abstract: Current pharmacotherapy of schizophrenia is based on targeted alternations mainly of serotoninergic and dopaminergic system by the second- eneration antipsychotics. Besides classic antagonism or partial agoni on dopamine D2 receptors, 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.

 

Czech Health Research Council 

The Interplay Between the Gut Microbiota and Brain Functions: Implication for Metabolome and Metabolic Syndrome in Schizophrenia (17-31852A)
Investigator: MUDr. Tomáš Páleníček, Ph.D.
Principle investigator: NIMH
Co-investigators/Partners: Institute of Animal Physiology and Genetics of the CAS (RNDr. Kateřina Fliegerová, CSc.); Institute of Microbiology of the CAS
Duration: 1.4.2017–31.12.2020
Total budget: 13 553 000 CZK
Total budget NIMH: 10 163 000 CZK
Abstract: Schizophrenia is a serious mental disease with high morbidity. The modern antipsychotics are effective in its therapy, but they may induce obesity and metabolic syndrome. Alteration in metabolism, changes in gut microbiota, gut barrier failure and low-grade chronic inflammation are all involved in pathogenesis of both schizophrenia and metabolic syndrome. Therefore, by analysis of microbiome, metabolome, gut barrier function and inflammatory response, new biomarkers for prediction of this serious therapy side-effect may be found. Moreover, by analyzing the key mechanisms in the pathogenesis of both conditions, this approach may even uncover suitable target for future therapy of schizophrenia or metabolic syndrome. We will use samples of blood, stool or urine, collected from patients with schizophrenia at the beginning of the antipsychotic treatment and after several months, when the presence or absence of the metabolic syndrome will be clearly apparent. Few animal experiments will be performed to identify the best possible targets before these will be used in full-scale investigation on humans.

Role of Frontotemporal Crosstalk in Cognitive Coordination and Flexibility Deficits in Schizophrenia: A Translational Study (17-30833A)
Investigator: Mgr. Tomáš Petrásek, Ph.D.
Principle investigator: Institute of Physiology of the CAS (prof. RNDr. Aleš Stuchlík, Ph.D.)
Co-investigator/Partner: NIMH
Duration: 1.4.2017–31.12.2020
Total budget: 12 990 000 CZK
Total budget NIMH: 8 045 000 CZK
Abstract: Disturbances of cognitive functions have been recognized as hallmarks of schizophrenia and predictors of therapeutic outcome. They significantly limit patient´s functioning, yet there are no specific treatments for cognitive deficits in this disease. In this translational project, we seek to determine the causal role of hippocampal-prefrontal projections in cognitive coordination and flexibility. Moreover, causative role of frontotemporal theta coherence and synchrony will be revealed by controlling PV+ interneuron activity in freely-moving rats. The human part will test relations of frontotemporal synchrony to coordination and flexibility in 35 remitted schizophrenia patients and 35 matched healthy controls using a hrEEG/fMRI measurements and tests of the virtual reality. The overall aim is to elucidate a neuronal substrate for cognitive deficits in schizophrenia for an intelligent design of new treatments. Results of this project will unequivocally show the constituents of frontotemporal dysfunction in schizophrenia and open way for future treatment of cognitive deficits.

 

The Ministry of the Interior of The Czech Republic

New Synthetic Drugs - Complex Interdisciplinary Research Centre (VI20172020056)
Investigator: MUDr. Tomáš Páleníček, Ph.D.
Principle investigator: University of Chemistry and Technology, Prague, Faculty of Food and Biochemical Technology (Ing. Martin Kuchař, Ph.D.)
Co-investigator/Partner: NIMH; Alfarma, s.r.o. (RNDr. Miroslav Flieger, CSc.)
Duration:1.1.2017–31.12.2020
Total budget: 42 761 000 CZK
Total budget NIMH: 24 462 000 CZK
Abstract: The project extends the current project VG20122015075. It focuses on datafillin NSDDB. Moreover, monitoring in the terrain, biological materials and identification of new synthetic drugs precursor. The addictive potential and mechanism of action (interaction with receptors and transporters, influence on brain neurobiological substrates) of the chosen representatives of NSD from different chemical groups will be evaluated. Information about NSD will be submitted for risk assessment in EMCDDA.

OPERATIONAL PROGRAMMES

OP Enterprise and Innovation for Competitiveness

Application of Industrial Biotechnology Methods for Differential Diagnostics of Neurological Diseases (CZ.01.1.02/0.0/0.0/17_176/0015497)
Investigator: RNDr. Jan Říčný, CSc.
Principle investigator: VIDIA spol. s r.o.
Co-investigator/Partner: NIMH
Duration: 1.7.2019–30.6.2022
Abstract: The aim of the project is the development of a multiparametric diagnostic kit and prototypes of autoantibody kits against selected antigens to be used in differential diagnostics, disease evaluation and response to treatment of selected neurological diseases - Alzheimer's disease, Parkinson's disease, Frontotemporal neurodegeneration, Lewy's dementia and Vascular dementia . Although the problems with aging of population is becoming increasingly urgent, there are currently no commercial kits to diagnose these neurodegenerations. The developed highly specific tests will create a new segment of diagnostic kits for use in the global market.

 

INTERNATIONAL PROJECTS

The Ministry of Education, Youth and Sports of The Czech Republic

Targeted Depletion of the TRP-VR1 in Murine Nociception Models for Treatment of Analgesics Resistant Pain (LTAB19024)
Investigator: Prof. Saak Victor Ovsepian, MD, PhD
Principle investigator: NIMH
Project Partner:  Technical University Munich and Helmholtz Zentrum Munich (Prof. Vasilis Ntziachristos)
Duration: 1.7.2019–31.12.2021
Abstract of the Czech part: There is major unmet need in developing effective and long-acting therapeutics for management of chronic, analgesic-resistant pain, including cancer pain. This project will apply a new genetic methodology developed by the Czech principal investigator for depletion of TRP-VR1 receptors in trigeminal nociceptors, to improve management of drug-resistant neuropathic and cancer pain in mouse models. IgG192 targeted lentivirus encoding VR1 shRNA will be used for retro-axonal depletion of TRP-VR1 pain sensing channels in trigeminal sensory neurons of mice in primary neuronal cultures and in vivo. Immunohistochemistry, biochemistry and confocal imaging will be used for verifying the effectiveness and specificity of VR1 depletion in trigeminal nociceptors. Reduced pain response will be confirmed using capsaicin-induced pain model in behaving animals, as well as specific molecular readouts such as expression of nuclear mGluR5 and phosphorylated-ERK1/2, Arc/Arg3.1 and c-fos. The new anti-nociceptive targeted vectors will be supplied to the German partner for its validation in cancer pain model, through the use of advanced methodologies for imaging dermal pain response as well as mapping brain response to pain in intact animals in vivo.
Abstract of the Bavarian part: The recently developed imaging methodologies such as raster-scanning optoacoustic mesoscopy (RSOM) will be utilized for detection of dermal nociceptive response to capsaicin-induced pain at the periphery. Multispectral optoacoustic tomography (MOST) on the other hand will be applied for mapping hemodynamic response in the brain in response to nociceptive inputs in intact animals in vivo. The effects of targeted anti-nociceptive vector depleting TRP-VR1 supplied by the Czech PI will be tested in capsaicin-induced pain models, as well as cancer pain model in mice produced by grafted subcutaneously with UM-SCC-104 (the human papillomavirus-16-positive head and neck Squamous Cell Carcinoma cells) into the sub-cutis of the external rostrum area of severe combined immunodeficiency (SCID). The anti-nociceptive effects of targeted VR1 in trigeminal ganglion neurons will be verified with RSOM and MSOT methods in vivo. The results of these studies will be rigorously tested versus controls, and correlated with data obtained by Czech principal investigator’s group using conventional immunohistochemistry and microscopic methods.

Dynamics of Hippocampal and Neocortical Neuronal Representations of Mutual Relationships between a Subject, Significant Moving Objects, and Environment (LTAUSA19135)
Principle investigator: RNDr. Eduard Kelemen, Ph.D.
Investigator: Prof. Saak Victor Ovsepian, M.D., Ph.D. Principle investigator: NIMH
Co-investigators/Partners: Institute of Physiology CAS; New York University (Prof. André A. Fenton), University of Arizona (Prof. Jean-Marc Fellous, Ph.D.)
Duration: 1.11.2019–31.12.2022
Total budget: 6 991 000 CZK
Total budget NIMH: 3 496 CZK
Abstract: Ability to orient and navigate in environment inhabited with moving objects, be it conspecifics, potential predators, prey or non-animate objects is crucial for survival and success in many animal species.  The main goal of the present project is to investigate in laboratory rat neural circuitry involved in controlling interaction with moving objects (conspecifics or a mobile robot) in an environment. The role of the hippocampus and neocortical areas in these cognitive processes has been already determined by our group. Now we plan to elucidate cellular and cell ensemble substrate of moving-goal navigation, which has so far remained relatively elusive. We aim to characterize patterns of activation of cortical networks in rats that are involved in processing interaction between the subject, moving objects and environments. We will use immediate early gene imaging and single cell ensemble electrophysiological approaches. To investigate causal relationship between neuronal activity patterns and rat’s interaction with moving objects we will use optogenetic manipulations of neocortical activity.

 

 

 

 


RP1 Experimental Neurobiology RP2 Public Mental Health RP3 Applied Neuroscience and Neuroimaging RP4 Epidemiological and Clinical Research in Addictions RP5 Sleep Medicine and Chronobiology RP6 Brain Electrophysiology RP7 Clinical Research of Mental Disorders RP8 Translational Neuroscience International Cooperation Department AD Centrum Publications Ongoing Projects Pharmaceutical Industry-Sponsored Research Ethics Commission Postgraduate Students Conferences & Seminars Awards International Course 2015
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