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Apoptosis of pancreatic β-cells induced by endoplasmic reticulum stress and its mechanisms in type 2 diabetes
Glatzová, Daniela ; Němcová, Vlasta (advisor) ; Libusová, Lenka (referee)
Increasing incidence of type 2 diabetes represents one of the principal threats to human health in the 21st century. Strong evidence indicates that the rise in incidence of type 2 diabetes is correlated with increasing levels of obesity and that important factor playing role in the development of this disease is an elevation in circulating glucose and fatty acids. Chronically increased concentration of these nutrients was shown to induce apoptosis of pancreatic beta-cells that subsequently contributes to diabetes progression. Despite intensive research, molecular mechanisms underlying this beta-cells loss are still unclear. However, there is increasing evidence that one of the key processes involved in glucose and fatty acid-induced beta-cell death is induction of endoplasmic reticulum stress. The aim of this work is to summarize the recent knowledge about induction of apoptosis by endoplasmic reticulum stress in pancreatic beta-cells in relation to type 2 diabetes.
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The role of structural motifs in the localisation of T-cell plasma membrane proteins
Glatzová, Daniela ; Cebecauer, Marek (advisor) ; Brábek, Jan (referee) ; Rozbeský, Daniel (referee)
Plasma membrane of T cells is abundant in diverse receptors and other molecules orchestrating immune responses. Numerous studies demonstrate that the localisation of proteins in the cell is non-random and that mislocalisation either in the context of plasma membrane at nanoscale or with respect to the cell interior can lead to the protein malfunction and subsequent aberrant T- cell response. In my first Ph.D. project we focused mainly on the role of the transmembrane domain length and amino acid composition, proximal sequences and the presence or absence of palmitoylation on the localisation of transmembrane adaptor proteins LAT, PAG and NTAL in T cells. We showed that plasma membrane localisation of PAG and NTAL is controlled by the amino acid composition of their TMD and is palmitoylation independent. We propose that NTAL localisation to the plasma membrane is, despite its suboptimal length, facilitated by the electrochemical asymmetry of its TMD. Among transmembrane adaptor proteins, LAT was the most interesting one. Dependency of LAT plasma membrane localisation on palmitoylation in combination with unusual amino acid composition of its TMD led us to investigate it in a separate project. My first author Ph.D. project was thus to elucidate the role of highly conserved helix-breaking amino acids,...
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Localisation of CD4 coreceptor and its variants in human T cells
Glatzová, Daniela ; Cebecauer, Marek (advisor) ; Drbal, Karel (referee)
CD4 co-receptor of main T cell receptor (TCR) is essential for proper development of T lymphocytes and their function in adaptive immune responses. It is believed that CD4 stabilizes the interaction of TCR with antigenic ligand, peptide-MHC, and thereby improves T cell-dependent responses during immune reaction. CD4 is transmembrane glycoprotein with a number of structural motifs in its intracellular domain which do not dramatically affect its sorting to the plasma membrane but can influence its local organization at nanoscale. CD4 was shown to transiently accumulate in the immunological synapse formed between T cell and antigen-presenting cell. Such accumulation is rapidly followed by its internalization and/or delocalization outside the synapse. This is in contrast with TCR which accumulates strongly in the immunological synapse and is later found enriched in the central area of this structure. It is therefore unclear how TCR and its CD4 co-receptor function together when binding to their common ligand during the initiation of signaling in T cells. We aim to study localization of CD4 at nanoscale using advanced fluorescence microscopy techniques achieving significant improvements in resolution. In this work, CD4 and its mutant variants, potentially causing its different localization at the...
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Apoptosis of pancreatic β-cells induced by endoplasmic reticulum stress and its mechanisms in type 2 diabetes
Glatzová, Daniela ; Němcová, Vlasta (advisor) ; Libusová, Lenka (referee)
Increasing incidence of type 2 diabetes represents one of the principal threats to human health in the 21st century. Strong evidence indicates that the rise in incidence of type 2 diabetes is correlated with increasing levels of obesity and that important factor playing role in the development of this disease is an elevation in circulating glucose and fatty acids. Chronically increased concentration of these nutrients was shown to induce apoptosis of pancreatic beta-cells that subsequently contributes to diabetes progression. Despite intensive research, molecular mechanisms underlying this beta-cells loss are still unclear. However, there is increasing evidence that one of the key processes involved in glucose and fatty acid-induced beta-cell death is induction of endoplasmic reticulum stress. The aim of this work is to summarize the recent knowledge about induction of apoptosis by endoplasmic reticulum stress in pancreatic beta-cells in relation to type 2 diabetes.
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