Targeted and Improved Alzheimer's Disease Drug Development
Support provider:
Technology Agency of the Czech Republic KAPPA Programme
Funded:
EEA grants
Norway grants
Investigator:
Main investigator:
University hospital Hradec Kralove, Czech Republic - assoc. prof. Ondrej Soukup, Ph.D.
Other investigators:
University of Oslo - Prof. Dr. med. Dr. rer. nat. Jens Pahnke E.F.N.
Institute of Experimental Medicine CAS - Mgr. Martin Horak Ph.D.
Bioinova, s.r.o. - MUDr. Peter Bauer Ph.D.
Abstract:
The aim of the project is the development of compounds for the treatment of Alzheimer´s disease (AD). The project will include an approaches of personalized medicine during the development process in the way that novel compounds will be tested in a disease in a dish (DiD) model derived from AD patients.
Project duration:
January 2021–April 2024
PET analyses of ABC transporter function for diagnostics and stratification of dementia patients
Support provider:
The Ministry of Education, Youth and Sports of the Czech Republic
Funded:
The EU Joint Programme – Neurodegenerative Disease Research (JPND)
Investigator:
Norway, Prof. Jens PAHNKE, University of Oslo (UiO)/Oslo University Hospital (OUS)
Germany, Prof. Peter BRUST, Helmholtz Zentrum, Dresden-Rossendorf (HZDR), LeipzigAustria, Prof. Oliver LANGER, Medical University of Vienna (MUV), Vienna
Latvia, Prof. Baiba JANSONE, University of Latvia (LU),Rīga
Czech, Prof. Ondřej SOUKUP, University Hospital Hradec Králové
France, Prof. Fabien GOSSELET, Université d’Artois, Lens
Sweden, Prof. Henrik BIVERSTÅL, Karolinska Institutet (KI), Stockholm
Abstract:
The blood-brain barrier (BBB) expresses different ATP-binding cassette (ABC) transporters, which control the access of endogenous and exogenous compounds from the blood into the brain as well as their removal from the brain into the blood. The export function of the BBB is of increasing importance and is moving continuously into the focus of research on neurodegenerative diseases (NDs). We have described for the first time that the ABC transporter C1 (ABCC1) is exceptionally important for the export of metabolites from the brain, especially for amyloid-β (Aβ) The aim to translate our new ABCC1 PET protocol to AD patients to assess whether cerebral ABCC1 function is impaired in comparison to age-matched healthy control subjects and to investigate the relevance of ABCC1 for the diagnostics of functional BBB-deficiency, which will allow better classification of patient groups. In parallel, we will extend our efforts toward ABCA7 and aim at developing the first PET radiotracers for imaging of ABCA7. These efforts will comprise several in vitro and in vivo investigations by using human and mouse cell culture BBB models (hPSC/iPSC-based and with specific knockout endothelia), humanized mouse models, chemical synthesis of new ABCA7 probes, morphological/toxicology analyses, ssNMR/cryo-EM, radiolabeling methods, and animal PET imaging. Following a precision medicine approach, the segregation of disease diagnoses/sub-diagnoses based on ABC transporter function may potentially enable targeted treatment studies for those patients who show transport deficiency. Moreover, the assessment of ABC transporter function may potentially allow for the stratification of patient populations for preventive interventions.
Project duration:
2021–2023
Development of Czech-Norwegian cooperation in the treatment of organophosphorus poisoning
Provider:
Norwegian Financial Mechanism 2009-2014 (7F16034)
Total grant received: 346 000 CZK
Investigator:
Ondrej Soukup
Abstract:
Organophosphate (OP) and warfare nerve agent- and pesticide- poisoning is a persistent world - wide problem, the latter alone with hundreds of thousand casualties every year. Informal cooperation between the Czech researchers and FFI researchers on countermeasures was already launched on an individual level in 2014. *The objective* of this project was to promote the cooperation to a robust collaboration on the institutional level to apply a common effort on the OP research. Thanks to the implementation of this Initiative and planned follow-up project, the involved institutions are now ready to cooperate at higher level in excellent basic research with high application potential in the long run.
- The First activity, a laboratory workshop at FFI, Norway, has helped Czech early-career stage researcher to learn advanced techniques of investigation within this field.
- The Second - a two-day workshop focused on the recent knowledge in the field of organophosphorus poisoning, current therapeutic approaches, underlying mechanisms and future perspectives in the treatment and research – had to be cancelled due cancelled flight from Oslo because of unfavourable weather conditions. Unfortunately, there was no possibility to postpone the activity due to the end of the Czech-Norwegian Programme. Part of the scheduled was postponed later in this year – meeting in Hradec Králové. Part of it has been accomplished via electronic communication – common project list (the Third activity) defining future goals and individual tasks within the consortium, and Memorandum of Understanding draft.
Project duration:
2017
Influence of new medicaments to structure-specific intristic flourescence of amyloid
Investigator:
Ondrej Soukup - FNHK, Danijela Rostohar - HiLASE, Carlos Serpa - University of Coimbra, Portugal
Abstract:
Increasing of life duration is link with increase of patient with dementia. Dementia is initiated by a variety of ailments and injuries that primarily or secondarily affect the brain. One of such diseases are Alzheimer. From more than decade is known that AD is connected with formation of plaques and tangles formed in the brain. Plague is made of amyloids Aβ 1-40 and 1-42. The affecting level of plaque increases long, up to 30 years, before clinical signs of AD appear. Understanding of modulators´s influencing acceleration, slow down or reversing the process of protein aggregation in neurodegenerative diseases is of a great importance for a development of possible medicaments and treatments. In the in vitro setup, aggregation is commonly assessed by using Thioflavin T, a fluorescent probe with a high affinity to Aβ polymers. However, this setup is limited by high degree of nonspecifity and from this point of view, intrinsic fluorescence of Aβ oligomers and polymers represents much reliable scientific tool for investigation of Aβ assembly.
According to all mentioned, the main objectives of proposed research will be:
a) Investigate intrinsic fluorescence of 2 different amyloid peptide (assembling Aβ 1-42 and non- assembling reversal Aβ 42-1)
b) Study kinetics of aggregation by measuring fluorescence decay curves
c) Study influence of novel potential drug candidate (a hybrid of tacrine and benzathiazol derivative) on the intrinsic fluorescence and on the kinetics of aggregation. Standard inhibitor will be used as a reference
d) To correlate findings with Thioflavine T test commonly used for assessment of Aβ assembly and with the microscopy findings
Project duration:
2017
Design, molecular modeling studies, synthesis and in vitro and in vivo essays of new oximes regenerative of acethylcholinesterase as antidotes against chemical warfare agents
Provider:
Brazilian government - Science without Boarders
Investigator:
Tanos Costa France – Institute of Military Engineering, Rio Dejaneiro, BrasilTeodorico C. Ramalho - Federal University of Lavras, Lavras, BrasilKamil Kuca – Biomedical Research Center, University Hospital Hradec Kralove, Czech Republic
Abstract:
Chemical and biological weapons (CB) are characterized by the potential of causing a large number of causalities with a psychological impact greater than the conventional weapons, based on high explosives. Despite the use of CB weapons in regular warfare today is unlikely, because they are banished by United Nations and controlled by the organizations for prevention of chemical and biological weapons (OPCW and OPBW), the simplicity and low cost of production has turned the development of this kind of weapon very attractive to terrorists and para-military groups.
Today no country in the World is in ideal conditions to face a CB emergency, but, surprisingly, no terrorist or para-military group has done efficient use of this kind of weapon in the last years. However, considering the current geopolitical situation, an incident of large proportions using CB weapons is just a matter of time. In this sense all efforts are valid to develop ways of detection, processes of decontamination and control, antidotes and treatments of response to CB emergencies.
The neurotoxic are the most lethal group among the chemical warfare agents. These compounds are able to inhibit the enzyme acethylcholinesterase (AChE), interrupting the transmission of nerve impulses at the synapses and provoking the so called cholinergic syndrome, that quickly leads to dead by cardio respiratory arrest. The cholinergic syndrome can be avoided by the action of oximes, molecules able to reactivate AChE. However, there is no oxime efficient against all known neurotoxic.
This project has the main goal of contributing to the development of new oximes as antidotes against the neurotoxic agents used in chemical warfare. The steps involved in the project are: 1) Studies by molecular modeling (MM) including docking, molecular dynamics and quantum mechanics/molecular mechanics (QM/MM), for the proposition of structures of new oximes; 2) Synthesis of the most promising structures; 3) In vitro and in vivo studies of these molecules. All the steps above will count on the advising of Prof Kamil Kuca from Check Republic, one of the leading experts in the World on this matter. The performance indicators of the project will be measured by the submission of manuscripts for publication in indexed journals, during the time of execution of the project, and the qualification of human resources. We expect to publish at least 01 paper in journal Qualis A CAPES for year of project, starting in 2015. Another indicator will be measured by eventual patent applications, expected for the last year of the project.
Project duration:
2014 - 2017
Biodosimetry using human blood lymphocytes mitochondrial DNA alterations
Provider:
National Institute of Health
Investigator:
Aleš Tichý
Abstract:
The increasing risk of acute large-scale radiation exposure of personnel (nuclear energetics, terrorism) requires the development of new biodosimetric tools that could provide rapid assessment of health effects and the correlation of estimated doses received. Hence, the development of new biomarkers of irradiation is emphasised, especially using high-throughput technologies.
Gamma-irradiation of the cells leads to oxidative stress, which impacts the nuclear DNA (DNA basis damage, DNA-protein cross-links, single/double strand breaks) but also the mitochondrial DNA (mtDNA). mtDNA is very sensitive to the oxidative stress and radiation-induced damage, which may result into insufficient DNA repair that persists long after irradiation and leads to genomic instability. Alterations in mtDNA copy number and the accumulation of large deletions are detectable by qRT-PCR. These parameters have already been described as suitable indicators of radiation damage in vitro. The proposed project aims to verify this hypothesis on peripheral blood lymphocytes of cancer patients receiving radiotherapy.
The aim is to determine the changes in mtDNA in peripheral blood lymphocytes of patients undergoing radiotherapy using specifically designed multiplex RT-PCR assay. The data will be compared with the analysis of dicentric chromosomes and apoptosis assessment in order to evaluate the suitability of this approach for high-throughput biological dosimetry.
Project duration:
1 August 2014 - 31 July 2015
