Projects / Programmes
Adverse outcome pathway leading to atherosclerosis
| Code |
Science |
Field |
Subfield |
| 3.06.00 |
Medical sciences |
Cardiovascular system |
|
| Code |
Science |
Field |
| B530 |
Biomedical sciences |
Cardiovascular system |
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
atherosclerosis, nanoparticles, coagulation factors, inflammation, cytokines, in vitro cell model, air-blood barrier, alveolar epithelium, macrophages
Researchers (12)
Organisations (2)
Abstract
Atherosclerosis is a chronic inflammatory disease causally linked to expression of pro-inflammatory cytokine interleukin 6 (IL‑6), which is expressed locally by different cells and tissues. Inhalation of nanoparticles in polluted air induces expression of the IL-6 by pulmonary macrophages, epithelial cells, and vascular endothelial cells. However, possible molecular events linking inhaled nanoparticles and IL‑6 to inflammation of vascular endothelium and subsequent fibrin clot formation remain unknown.
Here we propose to test hypothetical pathway, in which we propose that:
IL-6 expression is induced by coagulation factor Xa activated on membrane wrapped nanoparticles,
eventually leading to fibrin clot formation around the cell membrane wrapped nanoparticles. For this purpose, we will employ a newly proposed series of connected cell mono-culture in vitro models (CellNet) and fluorescence super-resolution microscopy STED technique.
Significance for science
Development of new treatments for cardiovascular disease
Since basic molecular mechanisms of cardiovascular disease (CVD) remain unresolved, United States environmental protection agency (US EPA), the National Institute of Health, and the European commission all recognize the need for increased priority for funding of basic research, which will elucidate molecular mechanisms involved in possible adverse outcome pathways of CVD. The results of the proposed research will therefore contribute to the development of new treatments for cardiovascular disease in general as well as caused by inhalation of polluted air.
Development of new in vitro models that will improve and replace current animal models
Since air-blood barrier is very similar to other epithelial/endothelial barriers, successful implementation of here proposed CellNet in vitro model will contribute to very much needed development of new in vitro models, which will replace current modes of testing effectiveness of new drugs and safety of new nano-particles used in different industrial applications. Namely, mouse models of disease are being recognized as very misleading, especially when exploring the immune system response, cancer, lung fibrosis, and heart disease, explaining why almost 95% of the drugs, which looked promising after experiments on mice, fail when subjected to clinical trials in humans.
Eropean Commission legislation is phasing out animal testing. More than €250 million was dedicated already during FP7 (2007-2013) to explore the alternatives. Horizon 2020 (H2020) further strengthened the funding to enhance human safety by validating animal-free methods for safety assessment of chemicals, food contaminants or nanomaterial. Joint Research Centre (JRC) of the European Commission clearly indicates the need for non-traditional methods such as in vitro and in silico tests. Although the need for alternatives to in vivo tests have been identified in Nature as high-level research “grand challenge” to reveal potential health impacts of new nanomaterials already in 2006, 10 years later in 2016 the same authors identified in Nature Nanotechnology that this research is still in its infancy despite some important advances in complex in vitro test systems, including physiologically relevant multiple cell-line systems.
Development of predictive toxicology
The development of the proposed CellNet in vitro model will contribute to the development of predictive toxicology. Every year, hundreds of new nanomaterials with unknown influence to human health are produced and it is virtually impossible to test all of them using classic approaches in toxicology. It is now believed that understanding of the adverse outcome pathways (AOPs) is the only way towards predictive toxicology elucidating the main events of the toxicity pathway to improve the prediction of the apical endpoints with alternative tests and possibly define the treatment and preventive strategies.
Significance for the country
Development of new treatments for cardiovascular disease
Since basic molecular mechanisms of cardiovascular disease (CVD) remain unresolved, United States environmental protection agency (US EPA), the National Institute of Health, and the European commission all recognize the need for increased priority for funding of basic research, which will elucidate molecular mechanisms involved in possible adverse outcome pathways of CVD. The results of the proposed research will therefore contribute to the development of new treatments for cardiovascular disease in general as well as caused by inhalation of polluted air.
Development of new in vitro models that will improve and replace current animal models
Since air-blood barrier is very similar to other epithelial/endothelial barriers, successful implementation of here proposed CellNet in vitro model will contribute to very much needed development of new in vitro models, which will replace current modes of testing effectiveness of new drugs and safety of new nano-particles used in different industrial applications. Namely, mouse models of disease are being recognized as very misleading, especially when exploring the immune system response, cancer, lung fibrosis, and heart disease, explaining why almost 95% of the drugs, which looked promising after experiments on mice, fail when subjected to clinical trials in humans.
Eropean Commission legislation is phasing out animal testing. More than €250 million was dedicated already during FP7 (2007-2013) to explore the alternatives. Horizon 2020 (H2020) further strengthened the funding to enhance human safety by validating animal-free methods for safety assessment of chemicals, food contaminants or nanomaterial. Joint Research Centre (JRC) of the European Commission clearly indicates the need for non-traditional methods such as in vitro and in silico tests. Although the need for alternatives to in vivo tests have been identified in Nature as high-level research “grand challenge” to reveal potential health impacts of new nanomaterials already in 2006, 10 years later in 2016 the same authors identified in Nature Nanotechnology that this research is still in its infancy despite some important advances in complex in vitro test systems, including physiologically relevant multiple cell-line systems.
Development of predictive toxicology
The development of the proposed CellNet in vitro model will contribute to the development of predictive toxicology. Every year, hundreds of new nanomaterials with unknown influence to human health are produced and it is virtually impossible to test all of them using classic approaches in toxicology. It is now believed that understanding of the adverse outcome pathways (AOPs) is the only way towards predictive toxicology elucidating the main events of the toxicity pathway to improve the prediction of the apical endpoints with alternative tests and possibly define the treatment and preventive strategies.
Most important scientific results
Interim report
Most important socioeconomically and culturally relevant results
