Researcher:
Göksel, Evrim

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PhD Student

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Evrim

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Göksel

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Göksel, Evrim

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2021 - 20237

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Researcher Of Publications: search.filters.isAuthorOfPublication.856cbf00-f63c-40e0-bbce-ea57f41746ea

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Now showing 1 - 7 of 7
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    A structured mechanical risk sensitivity assessment system using red cell deformability and fragmentation parameters
    (Ios Press, 2021) Yalçın, Özlem; Uğurel, Elif; Göktaş, Polat; Göksel, Evrim; Çilek, Neslihan; Atar, Dila; Faculty Member; Researcher; Researcher; PhD Student; PhD Student; Undergraduate Student; School of Medicine; School of Medicine; School of Medicine; Graduate School of Health Sciences; Graduate School of Health Sciences; School of Medicine; 218440; N/A; N/A; N/A; N/A; N/A
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    Activation of protein kinase a cascade increases deformability of sickle red blood cells
    (Ios Press, 2021) Connes, Philippe; Boisson, Camille; Renoux, Celine; Gauthier, Alexandra; Fort, Romain; Nader, Elie; Poutrel, Solene; Göksel, Evrim; Yalçın, Özlem; PhD Student; Faculty Member; School of Medicine; School of Medicine; N/A; 218440
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    Calcium/protein kinase C signaling mechanisms in shear-induced mechanical responses of red blood cells
    (Academic Press Inc Elsevier Science, 2021) N/A; N/A; N/A; N/A; N/A; N/A; Uğurel, Elif; Kısakürek, Zeynep Büşra; Aksu, Yasemin; Göksel, Evrim; Çilek, Neslihan; Yalçın, Özlem; Researcher; Undergraduate Student; Undergraduate Student; PhD Student; PhD Student; Faculty Member; School of Medicine; School of Medicine; School of Medicine; Graduate School of Health Sciences; Graduate School of Health Sciences; School of Medicine; N/A; N/A; N/A; N/A; N/A; 218440
    Red blood cell (RBC) deformability has vital importance for microcirculation in the body, as RBCs travel in narrow capillaries under shear stress. Deformability can be defined as a remarkable cell ability to change shape in response to an external force which allows the cell to pass through the narrowest blood capillaries. Previous studies showed that RBC deformability could be regulated by Ca2+/protein kinase C (PKC) signaling mechanisms due to the phosphorylative changes in RBC membrane proteins by kinases and phosphatases. We investigated the roles of Ca2+/PKC signaling pathway on RBC mechanical responses and impaired RBC deformability under continuous shear stress (SS). A protein kinase C inhibitor Chelerythrine, a tyrosine phosphatase inhibitor Calpeptin, and a calcium channel blocker Verapamil were applied into human blood samples in 1 micromolar concentration. Samples with drugs were treated with or without 3 mM Ca2+. A shear stress at 5 Pa level was applied to each sample continuously for 300 s. RBC deformability was measured by a laser-assisted optical rotational cell analyzer (LORRCA) and was calculated as the change in elongation index (EI) of RBC upon a range of shear stress (SS, 0.3-50 Pa). RBC mechanical stress responses were evaluated before and after continuous SS through the parameterization of EI-SS curves. The drug administrations did not produce any significant alterations in RBC mechanical responses when they were applied alone. However, the application of the drugs together with Ca2+ substantially increased RBC deformability compared to calcium alone. Verapamil significantly improved Ca2+-induced impairments of deformability both before and after 5 Pa SS exposure (p < 0.0001). Calpeptin and Chelerythrine significantly ameliorated impaired deformability only after continuous SS (p < 0.05). Shear-induced improvements of deformability were conserved by the drug administrations although shear-induced deformability was impaired when the drugs were applied with calcium. The blocking of Ca2+ channel by Verapamil improved impaired RBC mechanical responses independent of the SS effect. The inhibition of tyrosine phosphatase and protein kinase C by Calpeptin and Chelerythrine, respectively, exhibited ameliorating effects on calcium-impaired deformability with the contribution of shear stress. The modulation of Ca2+/ PKC signaling pathway could regulate the mechanical stress responses of RBCs when cells are under continuous SS exposure. Shear-induced improvements in the mechanical properties of RBCs by this signaling mechanism could facilitate RBC flow in the microcirculation of pathophysiological disorders, wherein Ca2+ homeostasis is disturbed and RBC deformability is reduced.
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    Phosphoproteomic changes in red blood cell membranes by Adenylyl cyclase/Protein kinase A signaling pathway and their roles on the mechanical stress responses of red blood cells
    (Ios Press, 2021) N/A; N/A; N/A; N/A; Uğurel, Elif; Çilek, Neslihan; Göksel, Evrim; Yalçın, Özlem; Researcher; PhD Student; PhD Student; Faculty Member; School of Medicine; Graduate School of Health Sciences; Graduate School of Health Sciences; School of Medicine; N/A; N/A; N/A; 218440
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    Signaling mechanisms in red blood cells: a view through the protein phosphorylation and deformability
    (Wiley, 2023) N/A; Çilek, Neslihan; Uğurel, Elif; Göksel, Evrim; Yalçın, Özlem; PhD Student; Researcher; PhD Student; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Sciences and Engineering; School of Medicine; Graduate School of Health Sciences; School of Medicine; N/A; N/A; N/A; 218440
    Intracellular signaling mechanisms in red blood cells (RBCs) involve various protein kinases and phosphatases and enable rapid adaptive responses to hypoxia, metabolic requirements, oxidative stress, or shear stress by regulating the physiological properties of the cell. Protein phosphorylation is a ubiquitous mechanism for intracellular signal transduction, volume regulation, and cytoskeletal organization in RBCs. Spectrin-based cytoskeleton connects integral membrane proteins, band 3 and glycophorin C to junctional proteins, ankyrin and Protein 4.1. Phosphorylation leads to a conformational change in the protein structure, weakening the interactions between proteins in the cytoskeletal network that confers a more flexible nature for the RBC membrane. The structural organization of the membrane and the cytoskeleton determines RBC deformability that allows cells to change their ability to deform under shear stress to pass through narrow capillaries. The shear stress sensing mechanisms and oxygenation-deoxygenation transitions regulate cell volume and mechanical properties of the membrane through the activation of ion transporters and specific phosphorylation events mediated by signal transduction. In this review, we summarize the roles of Protein kinase C, cAMP-Protein kinase A, cGMP-nitric oxide, RhoGTPase, and MAP/ERK pathways in the modulation of RBC deformability in both healthy and disease states. We emphasize that targeting signaling elements may be a therapeutic strategy for the treatment of hemoglobinopathies or channelopathies. We expect the present review will provide additional insights into RBC responses to shear stress and hypoxia via signaling mechanisms and shed light on the current and novel treatment options for pathophysiological conditions.
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    PublicationOpen Access
    A novel fragmentation sensitivity index determines the susceptibility of red blood cells to mechanical trauma
    (Frontiers, 2021) N/A; Yalçın, Özlem; Uğurel, Elif; Göktaş, Polat; Çilek, Neslihan; Atar, Dila; Göksel, Evrim; Researcher; PhD Student; Undergraduate Student; PhD Student; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Health Sciences; Graduate School of Sciences and Engineering; 218440; N/A; N/A; N/A; N/A; N/A
    Supraphysiological shear stresses (SSs) induce irreversible impairments of red blood cell (RBC) deformability, overstretching of RBC membrane, or fragmentation of RBCs that causes free hemoglobin to be released into plasma, which may lead to anemia. The magnitude and exposure tisme of the SSs are two critical parameters that determine the hemolytic threshold of a healthy RBC. However, impairments in the membrane stability of damaged cells reduce the hemolytic threshold and increase the susceptibility of the cell membrane to supraphysiological SSs, leading to cell fragmentation. The severity of the RBC fragmentation as a response to the mechanical damage and the critical SS levels causing fragmentation are not previously defined. In this study, we investigated the RBC mechanical damage in oxidative stress (OS) and metabolic depletion (MD) models by applying supraphysiological SSs up to 100 Pa by an ektacytometer (LORRCA MaxSis) and then assessed RBC deformability. Next, we examined hemolysis and measured RBC volume and count by Multisizer 3 Coulter Counter to evaluate RBC fragmentation. RBC deformability was significantly impaired in the range of 20-50 Pa in OS compared with healthy controls (p < 0.05). Hemolysis was detected at 90-100 Pa SS levels in MD and all applied SS levels in OS. Supraphysiological SSs increased RBC volume in both the damage models and the control group. The number of fragmented cells increased at 100 Pa SS in the control and MD and at all SS levels in OS, which was accompanied by hemolysis. Fragmentation sensitivity index increased at 50-100 Pa SS in the control, 100 Pa SS in MD, and at all SS levels in OS. Therefore, we propose RBC fragmentation as a novel sensitivity index for damaged RBCs experiencing a mechanical trauma before they undergo fragmentation. Our approach for the assessment of mechanical risk sensitivity by RBC fragmentation could facilitate the close monitoring of shear-mediated RBC response and provide an effective and accurate method for detecting RBC damage in mechanical circulatory assist devices used in routine clinical procedures.
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    PublicationOpen Access
    Proteomic analysis of the role of the adenylyl cyclase-cAMP pathway in red blood cell mechanical responses
    (Multidisciplinary Digital Publishing Institute (MDPI), 2022) Kağa, Elif; Yalçın, Özlem; Uğurel, Elif; Göksel, Evrim; Çilek, Neslihan; Researcher; PhD Student; PhD Student; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Health Sciences; 218440; N/A; N/A; N/A
    Red blood cell (RBC) deformability is modulated by the phosphorylation status of the cytoskeletal proteins that regulate the interactions of integral transmembrane complexes. Proteomic studies have revealed that receptor-related signaling molecules and regulatory proteins involved in signaling cascades are present in RBCs. In this study, we investigated the roles of the cAMP signaling mechanism in modulating shear-induced RBC deformability and examined changes in the phosphorylation of the RBC proteome. We implemented the inhibitors of adenylyl cyclase (SQ22536), protein kinase A (H89), and phosphodiesterase (PDE) (pentoxifylline) to whole blood samples, applied 5 Pa shear stress (SS) for 300 s with a capillary tubing system, and evaluated RBC deformability using a LORRCA MaxSis. The inhibition of signaling molecules significantly deteriorated shear-induced RBC deformability (p < 0.05). Capillary SS slightly increased the phosphorylation of RBC cytoskeletal proteins. Tyrosine phosphorylation was significantly elevated by the modulation of the cAMP/PKA pathway (p < 0.05), while serine phosphorylation significantly decreased as a result of the inhibition of PDE (p < 0.05). AC is the core element of this signaling pathway, and PDE works as a negative feedback mechanism that could have potential roles in SS-induced RBC deformability. The cAMP/PKA pathway could regulate RBC deformability during capillary transit by triggering significant alterations in the phosphorylation state of RBCs.