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Temple University

1. Gofman, Larisa. Role of Purinergic Receptor (P2X4) in EtOH-Mediated Microglial Immune Responses.

Degree: PhD, 2015, Temple University

Pathology

Ethanol (EtOH) abuse is the third leading cause of preventable death in the United States. Mounting evidence indicates that EtOH-induced neuropathology may result from multicellular responses in which microglia cells play a prominent role. Purinergic receptor signaling plays a key role in regulating microglial function and, more importantly, mediates EtOH-induced effects. In our current study we sought to determine the effects of EtOH on microglial cell function, specifically the role of purinergic receptor X4 (P2X4) in EtOH-mediated microglial responses. Our results show a significant up-regulation of P2X4 gene expression as analyzed by real-time qPCR and protein expression as analyzed by flow cytometry in embryonic stem cell-derived microglial cells (ESdM) after 48 hours of EtOH treatment, as compared to untreated controls. Calcium mobilization in EtOH treated ESdM cells was found to be P2X4R- dependent using 5-BDBD, a selective P2X4R antagonist. Blocking P2X4R signaling with 5-BDBD decreased the level of calcium mobilization compared to EtOH treatment alone. EtOH decreased migration of microglia towards fractalkine (CX3CL1) by 75% following 48 hours of treatment compared to control. CX3CL1-dependent migration was confirmed to be P2X4 receptor-dependent using the antagonist 5-BDBD, which reversed the effects as compared to EtOH alone. Similarly, 48 hours of EtOH treatment significantly decreased phagocytosis of microglia by 15% compared to control. 5-BDBD pre-treatment prior to EtOH treatment significantly increased microglial phagocytosis. These findings demonstrate that P2X4 receptor may play a role in modulating important regulatory functions in microglia in the context of EtOH abuse. P2X4R plays an important regulatory function in microglia. P2X4 is involved in a myriad of molecular signaling such as proliferation, activation of transcription factors, specifically through the MAPK pathway, and ATP signaling. Here, we also investigated the intracellular signal transduction pathway that influences P2X4R expression in microglia in response to EtOH. We found EtOH (100 mM) decreased phosphorylated AKT and extracellular signal-regulated kinase (ERK) cascades in ESdM cells. EtOH effect on ERK phosphorylation was completely inhibited by U0126, an inhibitor of MEK 1 and 2. However, PD98095, a potent inhibitor of MEK1 but a weak inhibitor of MEK2 had modest effect on phosphorylated ERK1/2 suggesting a possible role of MEK2-dependent ERK signaling in modulating EtOH induced effects on microglia. Utilization of 5-BDBD, a selective P2X4R antagonist reversed the EtOH-induced effect on phosphorylated AKT and ERK. Next we wanted to examine the effects of EtOH on transcription factor activity to determine the signaling mediators, which may play a role in EtOH-induced increase in P2X4R in microglia. EtOH increased transcriptional activity of NFκB, NFAT, and CREB,, however 5-BDBD blocked the effect on CREB transcriptional activity alone, suggesting a specific role of CREB in EtOH-induced expression of P2X4R in…

Advisors/Committee Members: Potula, Raghava;, Ramirez, Servio, Unterwald, Ellen M., Sawaya, Bassel E., Jordan-Sciutto, Kelly L.;.

Subjects/Keywords: Neurosciences;

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Gofman, L. (2015). Role of Purinergic Receptor (P2X4) in EtOH-Mediated Microglial Immune Responses. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,315641

Chicago Manual of Style (16th Edition):

Gofman, Larisa. “Role of Purinergic Receptor (P2X4) in EtOH-Mediated Microglial Immune Responses.” 2015. Doctoral Dissertation, Temple University. Accessed October 26, 2020. http://digital.library.temple.edu/u?/p245801coll10,315641.

MLA Handbook (7th Edition):

Gofman, Larisa. “Role of Purinergic Receptor (P2X4) in EtOH-Mediated Microglial Immune Responses.” 2015. Web. 26 Oct 2020.

Vancouver:

Gofman L. Role of Purinergic Receptor (P2X4) in EtOH-Mediated Microglial Immune Responses. [Internet] [Doctoral dissertation]. Temple University; 2015. [cited 2020 Oct 26]. Available from: http://digital.library.temple.edu/u?/p245801coll10,315641.

Council of Science Editors:

Gofman L. Role of Purinergic Receptor (P2X4) in EtOH-Mediated Microglial Immune Responses. [Doctoral Dissertation]. Temple University; 2015. Available from: http://digital.library.temple.edu/u?/p245801coll10,315641

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