The specificity of liver innate immune response for partial hepatectomy and laparotomy

The liver is the largest solid organ in the body with dual inputs for its blood supply. It receives 80% of its blood supply from the gut through the portal vein, which is rich in bacterial products, environment toxins, and food antigens. The remaining 20% is from vascularization by the hepatic artery. 70% of the cell number or 80% of the liver volume is composed of hepatocytes that fulfill the metabolic and detoxifying needs of the body. The remaining cells are made up of nonparenchymal cells, including endothelial cells, stellate cells, Kupffer cells, and lymphocytes. The liver successfully combines the role of a biochemical laboratory with the role of a major organ of innate immunity. In a physiologically relevant state, it eliminates antigens derived from the gastrointestinal tract, aging and transformed cells and reveals tolerance to their continuous presence. The liver responses by organ regeneration to partial hepatectomy and by acute phase response to any kind of body injury not affecting the liver. Our recent studies revealed the transient upregulation of interferon a (IFNa) expression during the early hours after partial hepatectomy. To unravel the potential role of IFNa in liver restoration we addressed the gene expression in primary hepatocytes isolated from control liver and cultivated with quasiphysiological dose of IFNa. ISGylation-related genes responsible for post-translational protein modification were the earliest up-regulated genes. Their expression and regulation after partial hepatectomy and laparotomy are in the centre of our attention. The unexpected results raised the question on the role of these genes in acute phase response and the mechanism of their IFNa independent regulation. The analysis of corresponding genes promoters with consequent chromatin immunoprecipitation is going on. The function of IFNa after partial hepatectomy is still an exciting challenge.

The role of interferon alpha in chemical synaptic transmission in central nervous system

The high-dose IFNa therapy is widely used for the treatment of hepatitis C, hematological malignancies, multiple sclerosis etc, and accompanied by side effects with largely undefined mechanisms of IFNa neurotoxicity. We applied self-elaborated tool COTRASIF (conservation-aided transcription-factor-binding site finder) for genome-wide bioinformatical search in rat and mouse genome for genes containing in their promoters IFN-stimulated response elements (ISRE) and discovered new putative target genes of IFNa, which encode the proteins involved in chemical synaptic transmission in central nervous system. The goal of the study is to verify the bioinformatical prediction and to find out the means to alleviate the IFNa therapy side effects on the basis of newly discovered and experimentally confirmed target genes of IFNa in central nervous system.

Transcriptional networks: understanding the logic of preeclampsia development

The human placenta is a unique temporal organ that originates from the trophectoderm of the blastocyst and develops into a complex functionally active structure that mediates the tight interactions between the fetus and the maternal organism. During the whole period of gestation placenta undergoes molecular, structural and functional rearrangements to meet the requirements of fetal and maternal organisms. The abnormalities in placental functions lead to the health problems for mother and child during gestation and after it. The syndrome of preeclampsia is one of the major complications of pregnancy (7 – 10% worldwide) and the leading cause of maternal and fetal morbidity and mortality. While the exact cause of preeclampsia remains unclear, there is strong evidence that a major cause predisposing a susceptible woman to preeclampsia is an abnormally implanted placenta yielding a state of hypoxia and increased oxidative stress, the release of anti-angiogenic proteins along with inflammatory mediators into the maternal plasma and generalized endothelial dysfunction.

We focus our research on two apsects - folate-related one-carbon unit metabolism as a basic metabolic systems in the cell and placental transcriptome during placental development in health and preeclampsia. The folate-related one-carbon unit metabolism is responsible for de novo biosynthesis of nucleic acid precursors, purines and pyrimidines, methionine and S-adenosylmethionine hence for the basic cellular processes as proliferation, differentiation, epigenetic regulation of gene expression, energy conservation and transport, co-enzymes synthesis, signal transduction and translation. Gene expression profiling provides the most global possible picture and the basis for inferring gene regulatory network. Analysis of the transcriptome of human placenta is used to understand the molecular mechanisms and signaling pathways controlling placenta development in health and preeclampsia.