Browsing by Subject "Primary cilia"
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Item Open Access Characterization of enteric nervous system response to disease conditions in intestine(Bilkent University, 2022-01) Gönüllü, Nagihan GizaySmall intestine is one of the vital organs in gastrointestinal tract that is responsible for absorption of food, amino acids and create barrier against microbial invasion. Whereas large bowel is involved in the reabsorption of water and minerals. Intestinal epithelium is a highly regenerative tissue that it can renew its cells in a span of 4-5 days. In homeostatic state, the turnover rate of the epithelial cells is stable however, in case of inflammation and disease, the rate of proliferation and differentiation increase to regenerate the damaged tissue. Primary cilia (PC) are non-motile, microtubule-based organelles that extrude from plasma membrane. It functions as a sensory element to detect environmental cues. One of the highly studied disease models is ulcerative colitis is mainly characterized by the inflammation of the intestinal mucosal layer and generated by DSS administration. Additionally, high fat diet induced obesity, as a metabolic disease model, was shown to affect intestinal stem cell activity such that higher fat composition of diet causes shortening of small intestine and decrease in weight of tissue. Enteric nervous system is the endogenous nervous network surrounding the gastrointestinal tract and it controls many vital functions including digestion, blood flow, intestinal motility. The initial aim of this study was to reveal the response of intestinal stem cell niche in those stated disease conditions. After detecting ACOT7 protein as a global marker for enteric nervous system of myenteric and submucosal plexus layers, we hypothesized that subpopulations of ENS cells have a connection with intestinal niche upon disease states. Our following goal was to identify subpopulations of ENS and ciliated cells. In order to assess our hypotheses, we conducted series of IHC experiments and confocal microscopy analyses. We found that ACOT7+ cells in ENS contain mainly distinct types of neuronal cell populations such as PHOX2B+ and HuCD+ cells. Further, we identified that glial cells are the main subpopulation of ENS changing their expression pattern in both colitis and obesity models. Also, we classified ciliated cells as a heterogenous population to be colocalized with several ENS and mesenchymal markers. Lastly, we analyzed the gut-brain axis response to DSS induced colitis in the brain of model animals with a focus on thalamus and insular cortex. We identified several thalamic regions showed similar expression pattern alterations which were observed in colon. Overall, the novelty of this thesis arises from the identification of ACOT7 as an ENS marker along with the detection of glial cell interaction with mesenchymal sub-populations. This interplay demonstrates a response upon disease states of both small intestine and colon.Item Open Access Hypothetical molecular interconnection between type 2 diabetes and Dyslexia(BioMed Central, 2021-10-21) Bülbül, Tuğba; Baharlooie, Maryam; Safaeinejad, Zahra; Güre, Ali Osmay; Ghaedi, KamranBackground: Dyslexia is one of the most common learning disabilities, especially among children. Type 2 diabetes is a metabolic disorder that affects a large population globally, with metabolic disorders. There have been several genes that are identified as causes of Dyslexia, and in recent studies, it has been found out that some of those genes are also involved in several metabolic pathways. For several years, it has been known that type 2 diabetes causes several neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease. Furthermore, in several studies, it was suggested that type 2 diabetes also has some associations with learning disabilities. This raises the question of whether “Is there a connection between type 2 diabetes and dyslexia?”. In this study, this question is elaborated by linking their developmental processes via bioinformatics analysis about these two diseases individually and collectively. Result: The literature review for dyslexia and type two diabetes was completed. As the result of this literature review, the genes that are associated to type 2 diabetes and dyslexia were identified. The biological pathways of dyslexia, and dyslexia associated genes, type 2 diabetes, and type 2 diabetes associated genes were identified. The association of these genes, regarding to their association with pathways were analysed, and using STRING database the gene associations were analysed and identified. Conclusion: The findings of this research included the interaction analysis via gene association, co-expression and protein–protein interaction. These findings clarified the interconnection between dyslexia and type 2 diabetes in molecular level and it will be the beginning of an answer regarding to the relationship between T2D and dyslexia. Finally, by improving the understanding this paper aims to open the way for the possible future approach to examine this hypothesis. © 2021, The Author(s).Item Open Access Identification of the fibrogenic cells in the liver(Bilkent University, 2022-03) Bozlar, MügeThe liver is an important multitasking organ with diverse functions to maintain body homeostasis. Adjustment of glucose level, detoxification, secretion of blood proteins, and synthesis of bile acids are the among these crucial functions. The fibrosis is one of the most common liver injury types. Although liver has a high capacity for regeneration via the proliferation of cells, this regeneration ability is directly dependent on the severity of fibrosis. One of the proliferative cells during fibrosis is cholangiocytes located around the portal triad. The cholangiocytes contain a primary cilium, a non-motile, ciliated organelle. The response of primary cilium to fibrosis is not well understood. The aim of this thesis was to characterize responses of cholangiocytes to liver fibrosis. For this purpose, TAA induced fibrosis model was generated for different weeks of samples, 16 weeks, 20 weeks, and 24 weeks in mice. IHC stainings and data collection from confocal microscopy were performed. According to our study, we observed that around the portal vein, big cell masses are formed and these cells are migrating between portal veins by following a path upon fibrosis. Moreover, several cells are escaping from this path and expanding through the central vein. The main contributors of these giant cell masses are cholangiocytes which keep their primary cilia under fibrotic conditions. Furthermore, we identified a new subpopulation of Arl13b+ cholangiocytes which are undergoing partial EMT by expressing mesenchymal markers such as Vimentin, CD34, and Pdgfra in these cell masses. During this process, they gain novel mesenchymal features at the same time they maintain their epithelial character. As a following goal, we wanted to identify components of these big cell masses, so niche components of partial EMT undergoing Arl13b+ cholangiocytes. We identified that Vimentin, CD34, and Pdgfra mesenchymal cells and Thy1+ portal fibroblasts (minority) are components of these massive cells in addition to homeostatic and partial EMT undergoing Arl13b+ cholangiocytes. As a final objective, we identified novel, possible markers for partial EMT undergoing Arl13b+ cholangiocytes and their niche components. To conclude, the novelties of this thesis were the demonstration of the primary cilium response against fibrosis, the identification of a new Arl13b+ cholangiocyte subpopulation undergoing partial EMT, and the characterization of components of the migratory big cell masses under fibrotic conditions.Item Open Access The primary cilia of the gastrointestinal tract in homeostasis and disease at the single-cell level(Bilkent University, 2021-07) Esen, DenizThe gastrointestinal tract is regularly renewed by stem cells which divide and differentiate into functionally and morphologically distinct cell types. Several key pathways, such as Wnt, Hedgehog and Bmp, regulate the cell fate. However, it remains a mystery how the associated signaling molecules are relayed between cells to coordinate stemness and differentiation cues. Primary cilia are small antenna-like organelles that harbors many receptors for these pathways. Here public single-cell RNA sequencing data is re-analyzed to show that primary cilia expression is heterogeneous in the intestinal mesenchyme and liver. Presence of primary cilia is also validated using immunofluorescence in the stroma and muscle cells of the mouse colon, using known markers of the primary cilia. Acot7 is identified as a primary cilium associated marker and found to be expressed in myenteric ganglia. In mice challenged with DSS to model ulcerative colitis, primary cilia are observed more abundant as the area covered by crypt structures become reduced due to the loss of epithelium. Acot7 expressing ganglial cells were observed more frequently and displayed morphological differences. Additionally, mice fed a high-fat diet over 16 weeks had shortening of the colon crypts and an increase in the primary cilia. This work suggests that primary cilia exist in the gastrointestinal tract during homeostasis and participate in inflammation and diet-based adaptations.