Pathogen-induced senescence as the initiation trigger for the onset of Alzheimer’s disease
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Dasa Bohaciakova, PhD (MUNI), Katerina Sheardova MD (FNUSA), Marie Vajrychova, PhD
Abstract:
Alzheimer´s disease (AD) is a progressive neurodegenerative disorder in the elderly population worldwide, underlaid by two pathological features in the AD brain: 1) extracellular beta-amyloid plaques (Aß) and 2) intraneuronal Tau-containing neurofibrillary tangles (P-Tau). However, clinical trials aiming to prevent P-Tau and/or Aß deposition failed to demonstrate the effectiveness of disease-modifying treatments. This implies that protein aggregation is perhaps not a cause but rather a consequence of unknown mechanism(s) that eventually lead to the AD pathology. Interestingly, it has been proposed that Aß peptides can also function as antimicrobial peptides as a part of innate immunity. And although they are normally protective, their accumulation can lead to the induction of senescence and senescence activated secretory phenotype (SASP) eventually leading to chronic inflammation, and degenerative pathologies. Such systemic SASP could be potentially detected from patients’ CSF or plasma samples and could be thus a relevant biomarker of early events that eventually lead to the development of AD. Therefore, here we aim to uncover novel biomarkers of AD by studying the molecular triggers leading to the onset of Alzheimer’s disease phenotype. We hypothesize that infection of the brain with pathogens is one of the initial triggers leading to the accumulation of Aß oligomers. This is then followed by induction of cellular senescence in neurons and/or glia that subsequently, via the production of SASP, leads to inflammation, neuronal loss, and dementia. By combining samples from clinically and biomarker well-defined patients, highly-sensitive analytical tools, the unique stem-cell-based model of cerebral organoids, and strong expertise in neurodifferentiation, senescence, and SASP, we will be able to identify novel factors that contribute specifically to the initiation of AD and translate this knowledge to discovering relevant AD biomarkers directly from CSF and/or blood.
Project duration:
1st May 2021–31st December 2024
Quantification of intra-amniotic inflammation in late preterm prelabour rupture of membranes associated with the response of amniotic fluid proteome
Junior
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Marie Vajrychova, PhD
Abstract:
Preterm prelabour rupture of membranes is associated with the risk of intra-amniotic inflammation even beyond 34 weeks of gestation (late PPROM). Currently, the determination of interleukin-6
(IL-6) in amniotic fluid is frequently used to confirm or reject the presence of intra-amniotic inflammation (IAI) in PPROM. However, there is a lack of information about the level of IL-6 associated with the global change of amniotic fluid proteome as a response to IAI. Hence, we employed a Tandem Mass Tag-based approach to uncover amniotic fluid proteome response to the presence of IAI in late PPROM. We believe that the correlation of IL-6 with the level of other proteins in amniotic fluid will better define the cut off value for IAI confirmation based on the level of IL-6 associated with the global change of amniotic fluid proteome and help to reveal women with the highest risk of excessive inflammatory response in late PPROM.
Project duration:
1st May 2021–31st December 2024
From hit-to-lead candidate – development of novel agents to combat tuberculosis
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Jan Korabecny, Jaroslav Roh
Abstract:
Tuberculosis (TB) remains a widespread infectious disease and one of the top 10 causes of death worldwide. Screening of our in-house library of small molecules identified new anti-TB lead candidate K1297 that acted in low micromolar range against M. tuberculosis. Hence, this project aims to develop new clinical candidates related to K1297 with respect to antimycobacterial activity in cellular and animal models. Given the structural simplicity of K1297 and the possibility of several feasible structural modifications, there is a high potential for the improvement of the biological properties of K1297. In particular, we will focus on in vitro biological properties of prepared compounds, mainly their anti-TB properties with stress on clinically isolated M. tuberculosis strains including multi- and extensively- drug-resistant strains; their mechanism of action, selectivity profile, cytotoxicity, genotoxicity risk, physicochemical characteristics, and in vivo profile of selected drug candidates including acute toxicity, pharmacokinetic and pharmacodynamic properties in a murine model of TB.
Project duration:
1-May-2021–31-December 2024
Dually acting cognitive enhancers for palliative treatment of Alzheimer´s disease
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Ondrej Soukup, Martin Horak, Karel Vales
Abstract:
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.
Project duration:
1-May-2020–31-December 2023
Smart biocompatible nanotools for a selective delivery of drug-siRNA cocktails for combination therapy of breast cancer
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Kamil Kuca, Vojtech Adam
Abstract:
Advances in understanding of cancer biology have only slowly been translated into improvements in cancer care. Among the main reasons belongs the lack of selective transport of anticancer drugs towards tumor tissue. With these limitations in mind, and in attempts to apply Paul Ehrlich´s "magic bullet" concept, liposomes and polymeric drugs were developed in 1960s. Recent developments in nanotechnologies are expected to improve drug delivery, primarily through enabling the drug solubilization,protection from degradation and decreasing the side effects. Nanomaterials can be functionalized with biomolecules, enabling to target specific cells within certain tissues or even specific organelles. However, only little improvements have been achieved in case of chemoresistant diseases, which is most likely due to inefficiency of cargo. Therefore, we propose to combine cutting-edge smart bionanotechnologies based on biocompatible protein nanocages – ferritins, with a heterogeneous cargo of short interfering RNA (to make cells vulnerable) and cytostatic drugs (a killing ingredient).
Project duration:
1-May-2020–31-December 2023
Development of novel quaternary ammonium compounds against microbial biofilm in oral cavity
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Jan Marek
Abstract:
In this project, we would like to prepare new antimicrobial compounds based on quaternary ammonium salts with strong effect against microbial biofilm of oral cavity (dental plaque). Biofilm cultures represent more resistant form of microorganisms that the planktonic (free-floating) one. The effectivity of disinfectants against biofilm is then significantly reduced despite the effectivity to the planktonic form of the same microorganisms is sufficient. The frequent occurrence of more microorganisms in symbiosis in biofilm arrangement is common. There is a high risk of emergence of dental caries, gingivitis or periodontitis at the long-term persistence of biofilm (dental plaque). The compounds of the quaternary ammonium salts type may significantly influence these processes and thus effectively reduce the formation of biofilms in oral cavity (dental plaque). It is necessary to point out to the differences in resistance of planktonic and plaque form of microorganisms.
Project duration:
1-May-2019–31-December 2022
Development of polyvalent decontamination mean
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Jan Marek, Daniel Jun
Abstract:
Project is aimed at the development of new combined micellar decontamination systems based on quaternary nitrogen compounds having detergent and active-decontamination properties, which will cause faster hydrolysis of chemical warfare agents. In the case of biological agents, these molecules are strong disinfectants, able to destabilize pathogen membrane structures. Several decontamination mixtures will be prepared and tested both in vitro and in vivo for their decontamination and disinfection properties against selected chemical and biological agents. The expected result of the project is efficient decontamination solution for personal skin decontamination with good tolerability.
Project duration:
1-May-2018–31-December 2021
Centrally acting antidotes for the treatment of organophosphorus poisoning
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Ondrej Soukup, Daniel Jun
Abstract:
Inactivation of acetylcholinestarse (AChE) in nerve and muscle by organophosphates is the toxic mechanism common to both nerve agents and pesticides. Standard countermeasures against OP poisoning involves muscarinic inhibition and the use of oxime a reactivator. The latter, however, is limited by a versatility ox oximes and by the low penetration of reactivators into the brain. The aim of this project is to develop oxime reactivators with better penetration of the blood brain barrier (BBB). Namely, monoquaternary oximes with balanced physico-chemical properties containing selected nuclophile capable of AChE reactivation and a ligand of peripherial anionic site ensuring the binding to the enzyme. Unique reactivators will be prepared and by application of series of in vitro and in vivo tests compounds will be evaluated and described. The best candidate of the preclinical development and with practical potential will be indentified.
Project duration:
1-April-2017–31-December 2020
Development of new environment friendly insecticides against malaria mosquito
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Kamil Musilek
Abstract:
Use of pesticides as a preventive measure is very important element in the integrated management approach to malaria and other vector-borne disease parasitoses. New acetylcholinesterase inhibitors, which will covalently bond to the insect specific cysteine, will be prepared. The synthesis of novel compounds and structure-biological activity relationship (SAR)
evaluation will be performed. The selected insectide candidates will be evaluated on safety after in vivo administration.
Project duration:
1-April-2016–31-December 2019
Biomedical photonic devices for advanced medicinal diagnostics and therapy
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Martin Kunes, Radka Czeczotkova, Jiri Paral, Pavel Peterka, Oleksiy Lyutakov
Abstract:
Proposed project involves development of novel optical system for fiber-optic based local monitoring, sensing and treatment. First, the material, to be inserted into the living mass (in-vivo experiment) will be biodegradable and biocompatible. This prevents the risk associated with traditional silica fiber. As the background, polymer blends and interpenetrating polymer networks will be used. Then, developed material will be used for construction of optical fiber and its connection with laser sources and detectors. Additionally, surface of optical fibers will be functionalized by susceptible layer for introducing the possibility for chemical analysis in-vivo. The safety and biocompatibility of developed system will be tested in a preclinical settings. Project combine specialists from different field of research and completely covered all stage of preparation of above mentioned system.
Project duration:
1-May-2015–31-December 2018
Development of multi-target drugs for Alzheimer´s disease: combination of AChE inhibitor and melatonin derivative
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Kamil Kuca, Jan Ricny
Abstract:
We would like to exploit the obtained preliminary data in preparation of more active hybrids combining derivative of melatonin and AChE inhibitor – huprine. Such compounds should exert multipotent profile in Alzheimer´s disease treatment by combining beneficial effect of mainly, but not exclusively, cholinergic enhancement and antioxidant activity. Funnel-like drug development process from design and synthesis though in vitro efficacy and safety evaluation to in vivo validation involving kinetic, toxic, pharmacodynamic and behavioral examination will be applied in order to select the best drug candidate. In this project, basic research (9%) represent the synthesis of novel compounds and the structure-biological activity relationship (SAR) evaluation. Applied research (91%) represents majority of the project, thus, the funnel-like selection of a drug candidate, its in vivo validation and subsequent patent protection application with commercial utilization.
Project duration:
1-May-2015–31-December 2018
Development of novel disinfectants against pathogens occuring in the hospital environment
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Ondrej Soukup (main investigator), David Malinak,Roman Prymula, Sarka Salajkova, Lenka Ryskova, Lenka Hobzova
Abstract:
In this project, we would like to develop new compounds based on quaternary ammonium salts with a strong disinfectant potential against nosocomial infections in hospital environment, thus bacterial, fungal and viral
pathogens. The project is designed for development of various (3-6) mixtures with strong disinfecting properties and wide spectrum of efficacy by combining individual agents with more specific efficacy. Developed mixtures also should not exert skin irritation at operating personnel, which will be ensured by in vitro and in vivo skin tests. Furthermore, variability of the mixtures and their alternating application should represent a tool for the controlling of microbial resistance. In this project, basic research (9%) represent the synthesis of novel compounds and
the structure-biological activity relationship (SAR)evaluation. Applied research (91%) represents majority of the project, thus, the funnel-like selection of a drug candidates, their in vivo safetyvalidation and subsequent patent protection application with subsequent application for patent protection.
Project duration:
1-May-2015–31-December 2018
Modulators of mitochondrial enzymes for treatment of neurodegenerative disorders
Provider:
Grant Agency for Health Research of the Czech Republic
Investigator:
Kamil Musilek, Rafael Dolezal, Martina Hrabinova, Martin Kunes, Ondrej Benek, Lukas Hroch
Co-investigator:
Zdenek Fisar, Jana Hroudova, Jiri Raboch
Abstract:
The mitochondrial enzymes seem to be next target for molecular design in term of Alzheimer Disease (AD) treatment. They are well known for their interaction with β-amyloid and they are subsequently responsible for disruption of cell homeostasis and cell death. The inhibition of β-amyloid interaction with mitochondrial enzymes by small modulators might prevent neuronal cell loss and thus improve progress of AD. Up-to-date, only few mitochondrial enzyme modulators were published and their design, synthesis and evaluation will be highly progressive in near future. The main aim of the project is development of convenient candidates (small molecules) for further preclinical research.
Project duration:
1-May-2015–31-December 2018
NT13599 - Characterization of the diagnostic potential of native polypeptides in amniotic fluid
Provider:
Ministry of Health
Investigator:
Juraj Lenčo, Marian Kacerovský, Vojtěch Tambor, Jana Žďárová Karasová
Abstract:
Preterm premature rupture of membranes (PPROM) is a principal cause of preterm births and considerably increases perinatal morbidity and mortality. The main reason is the causal link with intraamniotic infection (IAI), which occurs in 40-60% of PPROM patients. The most serious cases of IAI may result in fetal inflammatory response (FIRS) and cause permanent health consequences for the newborn or end up by the death of the fetus. FIRS is very often subclinical and thus frequently remains undetected. Currently, there is no tool for its precise prenatal diagnostics available. The project is focused on characterization of the diagnostic potential of native amniotic fluid polypeptides with regard to detection of IAI and FIRS.
Project duration:
1-April-2012 - 31-Dec-2015
NT14150 - Modulation of Colorectal Carcinoma by Biological Therapy - In Vitro Study
Provider:
Ministry of Health
Investigator:
Aleš Ryška, Stanislav John
Proteomics team - Biomedical Research Center
Abstract:
Resecated tumours from appropriate patients with colorectal carcinoma will be histopathologically examined and from the part of the tumour cancer cells will be obtained. First, the tumor cells will be cultured and the prepared cell cultures will be treated by bevacizumab and cetuximab. Subsequently, we will evaluate the changes in the phenotype of primary colorectal cancer tumor lines after stimulation with these agents in order to describe effect on the biological profile of the cells. Samples of these cell lines will be deeply frozen for the further proteomic analysis. Prospectively, in the second phase we would try to identify differences in proteome among the cell lines from patients who responded to the treatment by the particular drug from those where the treatment failed. As a result we would detect the differences both biological both proteomic which may be relevant for the future optimization and individualization of therapy.
Project duration:
1-May-2013 - 31-Dec-2015
Provider:
Ministry of Health
Investigator:
Marian Kacerovský, Ctirad Andrýs, Martin Procházka, Ondřej Šimetka, Petr Janků
Abstract:
Women with preterm prelabor rupture of membranes between gestational age 24 and 36 weeks will be included into the multicentre study. The intensity of inflammatory response (based on levels of cytokines and alarmins) and microbial load of Ureaplasma spp. will be determined in the cervical fluid. The placenta will be assessed for the signs of histological chorioamnionitis and funisitis after delivery. The inflammatory response in the cervical fluid will be characterized with respect to the presence of histological chorioamnionitis and funisitis with an ultimate goal to create a prediction model for these inflammatory complications. The relationship between microbial load of Ureaplasma spp. in cervical fluid and inflammatory response will be evaluated as well. Last goal will be to analyse the potential of microbial load of Ureaplasma spp. for the prediction of histological chorioamnionitis and funisitis.
Project duration:
1-May-2013 - 31-December-2015
Provider:
Ministry of Health
Investigator:
Jan Bureš, Daniel Jun, Marcela Kopáčová, Kamil Kuča, Martin Kuneš, Jaroslav Květina, Kamil Musílek, Stanislav Rejchrt, Ilja Tachecí, Jana Žďárová Karasová
Abstract:
Our research team will synthesise both priority compounds K203 and K027 (and reference asoxim and obidoxim) in sufficient volumes and supreme purity. Pharmacokinetics studies will set perspective therapeutic regimes (doses and rate of administration) and absorption gastrointestinal window. Bioavailability studies will determine biodistribution and effect / toxic exposition ratio in particular physiological systems. Investigation of motor functions of the upper gastrointestinal tract enables to evaluate possible therapeutic effect (against organophosphates poisoning) and possible side effects of acetylcholinesterase modulators to the gastrointestinal tract. The research team will use oesophageal impedance, pH-metry, high resolution manometry and electrogastrography. This is a priority and high impact society project.
Project duration:
1-May-2013 - 31-December-2015
