Assessment of efficacy and toxicity of biologically active substances – BioMolTox
Project holder:
Institute for Medical Research and Occupational Health (IMROH), Ksaverska cesta 2, Zagreb, www.imi.hr
Project leader: Nikolina Maček Hrvat, PhD, Senior Scientific Associate
Project duration:
1.1.2024. – 31.12.2027.
Funded by the European Union – Next Generation EU (Program Contract of 8 December 2023, Class: 643-02/23-01/00016, Reg. no. 533-03-23-0006)
Funded by the European Union – Next Generation EU. However, the views and opinions expressed are solely those of the author(s) and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the European Commission can be held responsible for them.
The BioMolTox project is focused on researching the mechanism of action of biologically active molecules that currently represent a general health problem such as organic pollutants, synthetic drugs, and nanoparticles, but also their complex mixtures that are present in the environment and organisms. Knowledge of the mechanism of action of these substances of natural and/or synthetic origin, to which we are exposed in the short or long term in our daily lives, is extremely important for assessing possible negative effects on human health and the environment.
Research directions:
1) Determining the effects of selected xenobiotics on a living organism.
2) Development and evaluation of the effects of potential new drugs.
3) Development and implementation of new research methods.
4) Biomonitoring of the population.
The multidisciplinarity of the project will enable a better characterization of the effects of selected biologically active substances using the methods of chemical analysis, enzyme kinetics, genetics, molecular toxicology, and toxicology in vivo.
The BioMolTox project follows the guidelines of the European Union, which include the protection of human health and the environment as one of the main objectives of the strategy for a sustainable climate-neutral, and circular economy.
The main goal of the project is to determine the mechanism of action and biological targets through a comprehensive analysis of the effects of biologically active substances of natural and/or synthetic origin and to assess the risks of harmful effects of these substances on the organism.
The research team of the project includes associates from the Division of Toxicology of the Institute for Medical Research and Occupational Health (IMROH), and collaborators from other institutions.
To implement the project as successfully as possible, the project is divided into five work packages (WP).
WP1: Influence of biologically active molecules on the nervous system
The research conceptualized in this work package is focused on studying the effects of organophosphorus compounds (OPs) used as pesticides and flame retardants or as nerve agents on the cholinergic system, on the development of new, more effective therapies for poisoning after acute and/or chronic exposure to OPs, and development of new potential drugs for the treatment of neurodegenerative diseases.
In the framework of RP1, we anticipate to:
i) Investigate the effect of selected OP compounds on the cholinergic system along with the development of new therapies for OP poisoning.
ii) Develop new molecules with pharmacologically important effects on the cholinergic system.
WP2: Development of advanced analytical methods for the characterization of biologically active molecules and assessment of their activity and toxicity using an integrated chemical-biochemical approach
The research conceptualized in this work package is focused on the effects of organic pollutants from the environment, naturally occurring mycotoxins, and new psychoactive substances, with a special emphasis on their interaction.
In the framework of WP2, we anticipate to:
i) Develop new analytical methods for identification and quantification of biologically active compounds (organic pollutants, psychoactive substances, mycotoxins, compounds designed as reversible cholinesterase ligands) and corresponding metabolites in biological samples (e.g. urine, blood, cell medium).
ii) Chemically-biochemically validate the mechanisms of action (redox processes, antioxidant/oxidation status, endocrine disruption) of biologically active compounds.
WP3: Development of advanced in vitro methods for evaluating the effectiveness and safety of complex mixtures of biologically active compounds
The research conceptualized in this work package is focused on the study of the biological effects of complex mixtures of organic pollutants and nanoparticles (NPs) and the development of in vitro methods for their monitoring. The focus is on the development of an innovative in vitro methodological platform for reliable risk assessment of complex mixtures containing NPs.
In the framework of WP3, we anticipate to:
i) Describe abiotic and biotic interactions of NPs within certain simulated experimental and biological matrices.
ii) Carry out testing, harmonization, and standardization of biochemical methods for evaluating the effectiveness and safety of complex mixtures with NPs.
WP4: Membrane transporters: key proteins in the disposition, efficacy, and toxicity of biologically active substances
The research conceptualized in this work package is focused on the study of the expression and function of membrane transporters of biologically active substances in experimental animal models in vivo/ex vivo and cell models in vitro.
In the framework of WP4, we anticipate to:
i) Investigate the expression and function of membrane transporters of biologically active substances at the level of mRNA and protein in cell lines in vitro and tissues/organs of experimental animals in vivo/ex vivo and analyze the role of membrane transporters in the metabolism of biologically active substances using cell lines that overexpress transporters.
ii) Implement a new type of research on the gene/protein expression of membrane transporters of biologically active substances in an experimental zebrafish model, develop new cell models for analyzing the effects of biologically active substances on membrane transporters, and establish a 3D cell culture model as a system for assessing the toxicity of biologically active substances.
WP5: Ecogenetic research in biomonitoring of populations, in vitro and in vivo conditions
The research conceptualized in this work package is aimed at assessing the genotoxic potential of biologically active molecules and monitoring the level of genomic damage, especially for sensitive human populations, to provide data for assessing the risk of malignant diseases and researching the protective effects of individual molecules to reduce negative effects known genotoxicants. The research includes ecogenetic studies and population biomonitoring.
In the framework of WP5, we anticipate to:
i) Determine the protective and cytotoxic/genotoxic effects of chemical substances and their mixtures and physical substances. ii) Establish a database necessary for science-based risk assessments of the human population exposed to dangerous biologically active molecules and/or chronic conditions and determine DNA damage reference values.