PROJECT 1: STUDY OF THE ROLE OF CELL HYDRATION IN REALIZATION OF BIOLOGICAL EFFECT OF NON IONIZING RADIATION (NIR) IN ISOLATED ENVIROMENTAL MODULE (IEM)
The environmental control from the point of public health is one of the main global problems for modern Life Sciences. The essential components of human occupational medium are ionizing and non-ionizing radiations. It is known, that biological effects of environmental factors depend on physicochemical characteristics of the medium as well as the initial functional state of cells and organisms. Therefore, for adequate estimation of biological effect of occupational medium on organism only biomarker can be used. However, at present such universal biomarker hasn’t been found yet. Our previous study allows us to consider cell hydration as a universal and extra sensitive biomarker for estimation of the biological effects of environmental factors including non-ionizing radiations (NIR). It has been hypothesized, that the changes of cell hydration serve as an input signal for intracellular metabolic cascade responsible for biological effect of environmental factors. This hypothesis is based on the fact, that cell membrane is highly permeable for water. As a result, the osmotic gradients on membrane have transient character and can be generated upon the impacts of extracellular and intracellular (metabolic) factors. The purpose of the present project is to check this hypothesis. As the problem of environmental control has a vital role for the personnel working in isolated environmental medium (IEM) like in submarine and space, in the present project the biological effects of NIR (infrasound frequency mechanical vibration (MV), static magnetic field (SMF), extremely low frequency electromagnetic fields (ELF EMF) and microwave (MW) on physicochemical properties of physiological solution (PS), plants cell hydration, microbes, DNA damage and repair, rat’s gut micro flora, cell hydration of brain and heart muscle tissues, cognitive function of brain, heart muscle contractility and xenopus oocytes injected with different mRNA, as well as impendancemetric determination of skeletal muscle hydration in IEM will be studied.
The project will consist of the following tasks:
1. NIR effect on physicochemical properties of physiological solution;
2. NIR effect on seaweed hydration and germination;
3. NIR effect on microbes;
4. NIR effect on DNA damage and repair in vitro and in vivo;
5. NIR effect on functional activity of rats;
a) brain tissues hydration and cognitive function,
b) heart muscle hydration and contractility,
c) gut micro flora,
d) xenopus oocytes, injected with different Na/K-ATPase isoforms-specific mRNA,
e) impedancemetric characteristics of skeletal muscle hydration.
The implementation of this project can use cell hydration as a universal biomarker for adequate detection of the biological effect of NIR on organisms in IEM, which can be used for estimation the life safety of the personnel working in submarine and space medium.
PROJECT 2: AGE-DEPENDENT MAGNETOSENSITIVITY OF RATS’ BRAIN CORTEX AND HEART MUSCLE TISSUES
Age-dependent magnetosensitivity of tissue hydration, dose-dependent [3H]-ouabain binding with cell membrane, 45Ca2+ exchange in brain cortex and heart muscle of rats in three aged (young, adult, old) groups are being studied. It is established that magnetosensitivity of tissue hydration depends on the initial level of its hydration. Age-dependent decrease of tissue hydration is due to Na+/K+ pump dysfunction. Therefore, the following studies are being performed:
1. Age-dependent magnetosensitivity of three populations of [3H]-ouabain receptors in cell membrane of different tissues (high, middle and low affinities).
2. The role of individual Na+/K+ pump isoforms-dependent signaling system in controlling cell hydration.
3. Age-dependent magnetosensitivity of Na+/K+ pump different isoform-dependent intracellular Ca homeostasis.
4. Age-dependent magnetosensitivity of Na+/K+ pump different isoform-dependent intracellular signaling system.
It is suggested that the implementation of the above mentioned project will allow to understand the nature of intracellular signaling system responsible for age-related medical (nerve and cardiovascular) disorders.
PROJECT 3: THE ROLE OF ATP-ase DEPENDENT INTRACELLULAR SIGNALING SYSTEM IN CARCINOGENESIS
At present, cancer is one of the major causes of death worldwide. However, the detail mechanism of carcinogenesis is not clear yet. There is a great number of hypotheses in this regard, but none of them could give a reliable explanation of the nature of primary mechanisms, the dysfunction of which leads to decontrolling of cell proliferation.
More than 80 years ago Warburg pointed out the loss of oxidative capacity of mitochondria in the cancerous cell. In these cells the glycolytic metabolism shift relative to oxidative phosphorylation even under aerobic conditions (Warburg 1956). However, until now the nature of primary mechanism the dysfunction of which leads to depression of mitochondrial function in cancer cells is unclear. Later it was shown that the uncoupling of oxidative and phosphorylation process leads to mitochondria swelling (Lehninger, 1962; Minkof & Damadian, 1976).
In 1971 Raymond Damadian had a revolutionary discovery in cancer research: it was shown that cancerous tissue is markedly over-hydrated and can be much as 90% water, while in norm it can be 70-73%. “Magnetic Resonance” method which was suggested by him for the detection of cell over hydration serves as an early tumor detection diagnostic method (Damadian, 1971) and at present has a worldwide clinical usage. However, the nature of metabolic mechanism controlling cell volume, the dysfunction of which causes overhydration in cancer cells is not elucidated. But it is well established that cell hydration is a fundamental dynamic parameter determining its functional activity which is realized by minimum two pathways a) by cell surface-dependent changes of the number of functional active proteins’ molecules (enzymes, receptors, carriers and channels) in membrane (Ayrapetyan, 1980, Ayrapetyan et al., 1984; Parton and Simons, 2007) and b) by the regulation of intracellular enzymes activity depending on protein “folding –unfolding” state (Minkof & Damadian, 1976; Parsegian, 2005).
Later more detailed investigation of the correlation between cell hydration and metabolic activity was established: cell swelling triggers proliferation, while cell shrinkage promotes the apoptosis (Haussinger et al., 1996; Lang, 2007; Hoffman et al., 2009). It was shown, that cell hydration causes not only the promotion of cell division and oncogene expression, but also inactivation of genes inducing cell apoptosis (McIntyre, 2006). On the basis of these data cell over-hydration was suggested as the primary messenger in carcinogenesis (Haussinger et al., 1996; McIntyre, 2006).
At the same time there is a great number of literature data that the increase of cell hydration can be the first transient step of cell death (Ling, 1984; Minkof & Damadian, 1976; Evans, 2008; Parry et al., 2007) which is followed by loosing intracellular water contents. In cancer cells this last phase is absent, that is, cell over-hydration has a continuous character (Damadian, 1971). Therefore, the elucidation of the mechanism, the dysfunction of which leads to decontrolling of cell volume, namely, over hydration in cancer cell is one of the key questions to understand the mechanism of carcinogenesis.
Therefore, in the project the following will be studied:
• Na+/K+ –ATPase isoforms-dependent signaling system controlling cell hydration and Carcinogenesis,
• Hyperactivity of Na+/K+ –ATPase and overexpression of its isoforms in Cancer cells,
• Cellular and molecular mechanisms of pM and nM ouabain effect on Cancer cells,
• The intracellular signaling system controlling [Ca2+]i in Normal and Cancer cells,
• The intracellular signaling system controlling [H+]i in Normal and Cancer cells,
• The interaction between Na+/K+–ATPase α3 isoform-dependent Na+/Ca2+ and Na+/H+ exchanges in Cancer cells,
• Na+/K+ –ATPase α3 isoform-dependent signaling system controlling cell hydration as a target for Cancer therapy,
• Cellular and molecular mechanisms of non-ionizing radiation effect on Carcinogenesis,
• Correlation between DNA methylation and α3 isoform synthesis
1. 1. PATENT N 2824 A
The Device for Measurement of Electrical Conductivity of Biological Tissues /2014/
Simonyan R., Deghoyan A., Ayrapetyan S.
2. PATENT N 2766 A
Bicyclic RNA Ca-Magnesium Complex Having Interferon-Inductive Properties /2013/
Aghabalyan A., Karagyozyan K., Ayrapetyan S., Zakharyan R.
3. PATENT N 2576 A
The Method of Melioration of Salty Lands /2011/
Mikayelyan Y., Barseghyan S., Mnatsakanyan N., Papinyan V., Ayrapetyan S.
4. PATENT N 2575 A
The Method of Microbiological Purification of Water /2011/
Martirosyan V., Ayrapetyan S.
5. PATENT N 2454 A
The Stimulation Method of Crops’ Germination and Growth Potential /2010/
Ayrapetyan S., Yeritspokhyants D
6. PATENT N 2353 A
Long Lasting Interferon Synthesis by Modified RNA Poly I:C /2010/
Aghabalyan A., Karagyozyan K., Ayrapetyan S., Zakharyan R.
7. PATENT N 2357 A
The Method of Water Purification /2010/
Ayrapetyan S., Moosavi E. S., Martirosyan V.
8. PATENT N 2352 A
The Activation Method of Bulls' Frozen Sperm Mobility /2010/
Baghdasaryan N., Ayrapetyan S.
9. PATENT N 2149 A2
The Inhibition Method of Sarcoma Growth and Development /2008/
Ayrapetyan S., Hakobyan K.
10. PATENT N I54400I
The Estimation Method of Neuronal Injury Caused by Radiation /1987/
Arvanov V., Ayrapetyan S., Dvoretcky A., Shayinskaya A.
11. PATENT N 1115436
New Chemical Compound Having Local Anesthetic Properties /1983/
Gevorgyan G., Gabrielyan S., Mnjoyan H., Durgaryan L., Vlasenko E., Ayrapetyan S., Suleymanyan M.