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| Author(s): |
Vinícius Rodrigues Silva
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2016-09-30 |
| Examining board members: |
Alan Stewart Hazell;
Andre Schwambach Vieira;
Cláudia Vianna Maurer Morelli;
Elizabeth Suchi Chen;
Tiago Campos Pereira
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| Advisor: | Alan Stewart Hazell |
| Abstract | |
The mechanisms that promote brain dysfunction after acute liver failure are not clearly understood. In the absence of treatment, the underlying pathophysiological basis of this process is unclear. Long noncoding RNAs are emerging as major regulators of cellular phenotypes, as well as the small noncoding RNAs known as microRNAs significantly control messenger RNA translation, normal and pathological functions in the mammalian body. Since their involvement in acute liver failure is currently unknown, we have currently profiled the expression of Long noncoding RNAs and microRNAs in the cerebral cortex of mice following treatment with azoxymethane. Groups of C57/BL6 mice (25-30 g) were treated with azoximetano (100 µg/g body weight, i.p.) and allowed to progress to the coma stage which occurred about 18 hours later, at which time the mice were sacrificed and the frontal cortex dissected out. Tissues was profiled at the genomic level for changes in the levels of long noncoding RNAs and microRNAs. Our findings in Long noncoding RNAs reveal that the glutamatergic synapse, JAK/STAT pathway, MAPK, Ras and mTOR was significant in the process of endocrine factors and other regulatory factors of calcium absorption as well as NF?B signaling pathway. They are some of the major pathways targeted by this category of RNA species. Our findings of microRNAs expression revealed 470 microRNAs profiled using microarrays, 37 were significantly altered (20 upregulated and 17 downregulated) in their expression in the acute liver failure group compared to sham group. Pathways analysis showed that many miRNAs altered after acute liver failure target multiple messenger RNAs that are part of various biological and molecular pathways. Glutamatergic synapse, Wnt signaling, MAP-kinase signaling, axon guidance, PI3-kinase-AKT signaling, T-cell receptor signaling and ubiquitin-mediated proteolysis are the major pathways targeted by the acute liver failure-sensitive microRNAs. At least 28 acute liver failure-responsive microRNAs targetted each of the above pathways. We hypothesize the alterations in microRNAs and their down-stream messenger RNAs of signaling pathways might play a role in the induction and progression of neurological dysfunction observed during acute liver failure. Altered expression of these pathways may have significant consequences in terms of development of the acute liver failure phenotype (AU) | |
| FAPESP's process: | 12/15660-3 - Role of altered glutamatergic neurotransmission in acute liver failure (ALF). |
| Grantee: | Vinícius Rodrigues Silva |
| Support Opportunities: | Scholarships in Brazil - Doctorate |