Thirty-eight-negative-kinase 1 (TNK1) is a major mediator of trauma induced intestinal injury and multi-organ failure
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PROVIDER: PRJNA484022 | ENA |
REPOSITORIES: ENA
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Project description:To check gene expression signatures in response to TNK1 expressionin intestine, we performed whole genome microarray on intestinal (ileum) epithelial cells purified from TNK1 expressing and not expressing mice
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Project description:Dysregulated intestinal epithelial apoptosis initiates gut injury, alters the intestinal barrier, and can facilitate bacterial translocation leading to a systemic inflammatory response syndrome (SIRS) and/or multi-organ dysfunction syndrome (MODS). A variety of gastrointestinal disorders, including inflammatory bowel disease, have been linked to intestinal apoptosis. Similarly, intestinal hyperpermeability and gut failure occur in critically ill patients, putting the gut at the center of SIRS pathology. Regulation of apoptosis and immune-modulatory functions have been ascribed to Thirty-eight-negative kinase 1 (TNK1), whose activity is regulated merely by expression. We investigated the effect of TNK1 on intestinal integrity and its role in MODS. TNK1 expression induced crypt-specific apoptosis, leading to bacterial translocation, subsequent septic shock, and early death. Mechanistically, TNK1 expression in vivo resulted in STAT3 phosphorylation, nuclear translocation of p65, and release of IL-6 and TNF-α. A TNF-α neutralizing antibody partially blocked development of intestinal damage. Conversely, gut-specific deletion of TNK1 protected the intestinal mucosa from experimental colitis and prevented cytokine release in the gut. Finally, TNK1 was found to be deregulated in the gut in murine and porcine trauma models and human inflammatory bowel disease. Thus, TNK1 might be a target during MODS to prevent damage in several organs, notably the gut.
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Project description:#G017 Burn/Trauma Study. This is a Glue Grant Study comparison between gene expression analyses performed in eight trauma/burn subjects using either a buffy coat isolation of whole blood or using the PAXgene system Keywords: other
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Project description:While the paradigm that genetic predisposition and environmental exposures interact to shape development and function of the human brain and ultimately the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not been elucidated yet. Here we show that a functional polymorphism altering chromatin interaction between the transcription start site and long range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increases the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements (GREs) of FKBP5. This demethylation is linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global impact on the function of immune cells and brain areas associated with stress regulation. This first identification of molecular mechanisms of genotype-directed long-term environmental reactivity will also critically contribute to designing more effective treatment strategies for stress-related disorders. Effects of FKBP5 rs1360780 genotype x environment interaction on peripheral blood mRNA expression of GR responsive genes, as measured by gene expression arrays, were explored in 129 individuals (child abuse/risk allele carrier N = 40, child abuse/protective allele carrier N = 15; and no child abuse/risk allele carrier N = 60, no child abuse/protective allele carrier N = 14). In all 129 individuals, 1627 transcripts showed a significant correlation with plasma cortisol concentrations, suggesting their GR responsiveness. The correlation of 76 of these transcripts with cortisol plasma levels showed significant differences when stratifying by FKBP5 genotype in individuals with child abuse (Fisher z score ≥ 1.96) For these 76 transcripts, the mean absolute correlation coefficient with plasma cortisol was R = 0.23 in the risk allele carriers with child abuse, that is those exhibiting a demethylation of FKBP5 intron 7 as compared to R = 0.74 in the carriers of the protective genotype with child abuse where intron 7 methylation remains largely stable. This indicates a relative GR-resistance in the trauma exposed FKBP5 risk allele vs. protective genotype carriers. These 76 transcripts did not show a genotype-dependent difference in correlation coefficients in non-trauma exposed individuals suggesting that exposure to early trauma enhances FKBP5 genotype-dependent effect of GR sensitivity, most likely by epigenetic mechanisms. These findings suggest that the combination of FKBP5 risk allele carrier status and early trauma exposure alters the stress hormone-dependent regulation of several genes in peripheral blood cells, and might thereby enhance the reported association of early trauma with immune and inflammatory dysregulation, further promoting system-wide symptoms of stress-related disorders.
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Project description:#G017 Burn/Trauma Study. This is a Glue Grant Study comparison between gene expression analyses performed in eight trauma/burn subjects using either a buffy coat isolation of whole blood or using the PAXgene system
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Project description:Physiological, anatomical, and clinical laboratory analytic scoring systems (APACHE, Injury Severity Score (ISS)) have been utilized, with limited success, to predict outcome following injury. We hypothesized that a peripheral blood leukocyte gene expression score could predict outcome, including multiple organ failure, following severe blunt trauma. Contributor: The Inflammation and the Host Response to Injury Large Scale Collaborative Research Program Keywords: expression profiles
2009-04-13 | GSE11375 | GEO
Project description:Physiological, anatomical, and clinical laboratory analytic scoring systems (APACHE, Injury Severity Score (ISS)) have been utilized, with limited success, to predict outcome following injury. We hypothesized that a peripheral blood leukocyte gene expression score could predict outcome, including multiple organ failure, following severe blunt trauma. Contributor: The Inflammation and the Host Response to Injury Large Scale Collaborative Research Program Keywords: expression profiles cRNA derived from whole blood leukocytes obtained within 12 hours of hospital admission provided gene expression data for the entire genome that were used to create a gene expression score for each patient. Expression profiles from healthy volunteers were averaged to create a reference gene expression profile which was used to compute a difference from reference (DFR) score for each patient. This score described the overall genomic response of patients within the first 12 hours following severe blunt trauma. Regression models were used to compare the association of the DFR, APACHE and ISS scores with outcome.
2009-04-12 | E-GEOD-11375 | biostudies-arrayexpress
Project description:Trauma represents a major socioeconomic burden worldwide. After a severe injury, hemorrhagic shock (HS) as a frequent concomitant aspect is a central driver of systemic inflammation and organ damage. The kidney is often strongly affected by traumatic-HS, and acute kidney injury (AKI) poses the patient at great risk for adverse outcome. Recently, thirty-eight-negative kinase 1 (TNK1) was proposed to play a detrimental role in organ damage after trauma/HS. Therefore, we aimed to assess the role of TNK1 in HS-induced kidney injury in a murine and a post hoc analysis of a non-human primate model of HS comparable to the clinical situation. Mice and non-human primates underwent resuscitated HS at 30 mmHg for 60 min. 5 h after the induction of shock, animals were assessed for systemic inflammation and TNK1 expression in the kidney. In vitro, murine distal convoluted tubule cells were stimulated with inflammatory mediators to gain mechanistic insights into the role of TNK1 in kidney dysfunction. In a translational approach, we investigated blood drawn from either healthy volunteers or severely injured patients at different time points after trauma (from arrival at the emergency room and at fixed time intervals until 10 days post injury; identifier: NCT02682550, https://clinicaltrials.gov/ct2/show/NCT02682550). A pronounced inflammatory response, as seen by increased IL-6 plasma levels as well as early signs of AKI, were observed in mice, non-human primates, and humans after trauma/HS. TNK1 was found in the plasma early after trauma-HS in trauma patients. Renal TNK1 expression was significantly increased in mice and non-human primates after HS, and these effects with concomitant induction of apoptosis were blocked by therapeutic inhibition of complement C3 activation in non-human primates. Mechanistically, in vitro data suggested that IL-6 rather than C3 cleavage products induced upregulation of TNK1 and impaired barrier function in renal epithelial cells. In conclusion, these data indicate that C3 inhibition in vivo may inhibit an excessive inflammatory response and mediator release, thereby indirectly neutralizing TNK1 as a potent driver of organ damage. In future studies, we will address the therapeutic potential of direct TNK1 inhibition in the context of severe tissue trauma with different degrees of additional HS.
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Project description:The mortality rate for patients with trauma is 5.8 million per year. For people aged 15-49, trauma is one of the three leading causes of death. Activation of the coagulation system, intractable hypoxemia, infections and acidosis accompanying post-traumatic patients cannot be separated from trauma immunization. The purpose of this research is to understand the expression of immune cells in patients after trauma, especially severe multiple injuries, and to construct an immune cell profile of patients with multiple injuries.
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