A sample of colorectal carcinoma is obtained by laser microdissection from a histological preparation of gut epithelium.
Our research is focused on biology, physiology and pathophysiology of the intestine and cellular and molecular mechanisms of corticosteroid regulations. To achieve the aims, our group utilizes wide range of experimental approaches including biochemical analysis (i.e. determination of enzyme activities), genomic and proteomic techniques, microanatomy (laser microdissection) and electrophysiologic techniques (voltage clamp). To elucidate the mechanisms operating under normal and pathological conditions we use specific rat strains with weak and strong HPA axis activity (Fisher 344 and Lewis rats), germ-free animals and animal models of colitis, arthritis and colitis-associated colorectal cancer. Ongoing research topics in our group focus on the elucidation of:
- Effect of psychosocial stress on HPA axis regulation
- Effect of inflammation on local metabolism of glucocorticoids in neuroendocrine regulatory pathways and secondary lymphoid organs
- Role of internal time-keeping system in pathogenesis of colorectal cancer associated with inflammatory bowel disease
- Effect of gut microbiota on neuroendocrine regulatory pathways during stress
- Regulation of intestinal transport
Projects
Stress, a widespread condition of modern society, activates the hypothalamus-pituitary-adrenal (HPA) axis, which results in upregulation of plasma level of glucocorticoid hormones (cortisol in human, corticosterone in rats and mice). The activity of HPA axis is regulated by a variety of negative feedback mechanisms including self-regulation by its end products cortisol and corticosterone, whose local concentration is modulated by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11HSD1). This enzyme elevates local (intracellular) concentration of biologically active form of glucocorticoid hormone due to reduction of biologically inactive corticosteroid derivatives presented in blood plasma. Our aim in this project is to explore the potential role of 11HSD1 in regulation of HPA axis in stressed rat.
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The functions of the gastrointestinal tract are controlled by a variety of regulatory networks including hormone, neural and immune signaling. These regulatory networks are essential for complex coordination of events that integrate barrier functions, digestion and transport with alterations in motility and the flow of blood and lymph in response to the daily fasting-feeding cycle and to the other physiological and pathophysiological conditions. The aim of this project is to analyze the changes of intestinal transport functions under normal and pathological conditions.
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There is growing evidence that gut microbiota have a modulatory effect on behavioral, neurochemical and immunological responses, especially on postnatal development of stress response and stress-related psychiatric disorders, often comorbid with a variety of other illnesses including diseases of the gastrointestinal tract. The purpose of this project is to clarify mechanisms of action involved in the effects of gut microbiota on brain neurochemistry, behavior and activation of the hypothalamus-pituitary-adrenal axis.
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Epidemiologic studies demonstrate that disturbed circadian rhythms, often observed in time-shift workers, are significantly associated with a higher cancer risk. The aim of this project is to identify the relationship between disruption of the internal time keeping system and cancer. These studies are of importance not only for understanding the ethiology of the disease but they are also of great significance for precaution of cancer and probably also for the effectiveness of cancer therapy (chronotherapy).
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Glucocorticoids exert anti-inflammatory and immunomodulatory effects that may be regulated in part by the activities of the glucocorticoid-activating and -inactivating enzymes, 11β-hydroxysteroid dehydrogenase type 1 (11HSD1) and type 2 (11HSD2), respectively. Exposure to proinflammatory stimuli such as TNF-α and IL-1β increases 11HSD1 in some cells, while inducing a decrease of 11HSD2 in others. These findings indicate that changes in 11HSD activity induced by proinflammatory cytokines might contribute to the feedback regulation of inflammation. The aim of the project is therefore to improve our understanding of the role of 11HSDs in inflammation.
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Publications
Vodička, Martin - Ergang, Peter - Hrnčíř, Tomáš - Mikulecká, Anna - Kvapilová, Pavlína - Vagnerová, Karla - Šestáková, Blanka - Fajstová, Alena - Hermanová, Petra - Hudcovic, Tomáš - Kozáková, Hana - Pácha, Jiří
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Microbiota affects the expression of genes involved in HPA axis regulation and local metabolism of glucocorticoids in chronic psychosocial stress
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Brain Behavior and Immunity 2018, 73(Oct 2018), 615-624
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IF = 6.306
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Kolínská, Jiřina - Zákostelecká, Marie - Zemanová, Zdeňka - Lisá, Věra - Goliáš, Jaroslav - Kozáková, Hana - Dvořák, B.
Cellular differentiation of non-transformed intestinal epithelial cells is regulated by Lactobacillus rhamnosus and L. casei strains
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Physiological Research 2018, roč. 67, 2, p. 261-273
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IF = 1.324
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Ergang, Peter - Mikulecká, Anna - Vodička, Martin - Vagnerová, Karla - Mikšík, Ivan - Pácha, Jiří
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Social defeat stimulates local glucocorticoid regeneration in lymphoid organs
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Endocrine Connections 2018, 7(12), 1389-1396
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IF = 3.041
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Polidarová, Lenka - Houdek, Pavel - Sládek, Martin - Novosadová, Zuzana - Pácha, Jiří - Sumová, Alena
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Mechanisms of hormonal regulation of the peripheral circadian clock in the colon
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Chronobiology International. 2017, roč. 34, 1, p. 1-16
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IF = 2.643
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Ergang, Peter - Vodička, Martin - Vagnerová, Karla - Moravec, Martin - Kvapilová, Pavlína - Kment, M. - Pácha, Jiří
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Inflammation regulates 11 beta-hydroxysteroid dehydrogenase type 1 differentially in specific compartments of the gut mucosal immune system
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Steroids. 2017, roč. 126, Oct 2017, p. 66-73
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IF = 2.523
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Isolated colonic crypt of rat.
Intracellular pH response in isolated colonic crypts of rat. The crypts were exposed to intracellular alkalinization by addition of NH4Cl followed by acidification after washing out the ammonium pulse.
