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The role of the endoplasmic reticulum stress in the development of pathologies, their prevention and treatment

Work number - M 1 AWARDED

Presented Institute of Biochemistry of the National Academy of Sciences of Ukraine

Dr. Viletska Y.M., Dr. Khita O.O.

This work is devoted to the study of stress-dependent molecular mechanisms of obesity with its metabolic complications and oncogenesis, which are common diseases today, by studying gene expression in human cells. These are genes that encode key factors of proliferation, angiogenesis and oncogenes, as well as proteins that control mitochondrial function.

For the first time it was found that under conditions of obesity in the subcutaneous adipose tissue of men the expression of genes of the main factors of angiogenesis was decreased, but the expression of oncogenes and growth factors was up-regulated, which can lead to oncotransformation. It was also found that the expression of stress-mediating factors of the endoplasmic reticulum was differentially changed under obesity, and the insulin resistance development is accompanied by a decreasing of the expression of a large group of genes controlling key metabolic processes. Under obesity, the level of a number of microRNAs that control the expression of key regulatory genes is also reduced. The results indicate an important role of changes in the expression of these key factors in the development of obesity, as well as its metabolic and other complications by reprogramming the genome due to stress of the endoplasmic reticulum. Moreover, the development of insulin resistance dramatically reduces the body's immune defenses, as confirmed by the patent for the invention. In addition, it has been shown that different nanoparticles initiate the endoplasmic reticulum stress leading to the development of genotoxicity and a sharp decrease in immune protection. It was also developed methods for predicting the negative impact of nanomaterials on the body and its immune system by the evaluation of the expression of HLA-DRA and HLA-G genes.

It was also shown that the expression of all studied genes of mitochondrion was dependent to the function of IRE1 signaling protein, which mediates the most conservative endoplasmic reticulum stress pathway, in glioma cells, indicating a possible contribution of these genes to the anti-proliferative effect of IRE1 inhibition. It was found that stress-dependent regulation of these genes can be mediated by both protein kinase and endoribonuclease activities of IRE1. Inhibition of the functional activity of the IRE1 signaling protein has been shown to reduce the proliferative potential of glioma cells by altering the expression of a number of oncogenes and tumor suppressors, and by reprogramming the effect of key factors of tumor growth, such as hypoxia, glucose deficiency, or glutamine deficiency on the expression of most studied genes.

Number of publications: 26 articles, including 10 articles in English-language journals with an impact factor. The total number of references to the authors' publications / h-index of work, according to the databases is respectively: Web of Science - 3/2, Scopus - 44/8, Google Shcolar - 105 / 13. Received 6 patents of Ukraine, 2 of them for inventions.