رسالة جامعية
Hsp90 Regulates the NLRP3 Inflammasome via the NF-kB Signaling Pathway
| العنوان: | Hsp90 Regulates the NLRP3 Inflammasome via the NF-kB Signaling Pathway |
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| المؤلفون: | Sparksman, Steven |
| المساهمون: | Beck, Paul, Muruve, Daniel, MacDonald, Justin, McKay, Derek, Braun, Janice |
| بيانات النشر: | Cumming School of Medicine University of Calgary |
| سنة النشر: | 2020 |
| المجموعة: | PRISM - University of Calgary Digital Repository |
| مصطلحات موضوعية: | DMAG, 17-DMAG, Hsp90, SGT1, NLRP3, C. diff, Co-IP, AGK2, Clostridium difficile, HEK293, HEK293T, LPS, Lipopolysaccharide, NALP3, PLA, Immunofluorescence, Proximity Ligation Assay, Nigericin, PMA, Phorbol 12-Myristate 13-Acetate, SIRT2, THP-1, THP1, TcdA, TcdB, MMP9, ZVAD, Z-VAD-fmk, Inflammasome, Cytokine |
| الوصف: | An over-reactive inflammatory response can lead to chronic inflammation and auto-immune disorders such as Crohn’s disease, ulcerative colitis or cancer. At the heart of the host’s inflammatory response is an immune cell intracellular sensor protein known as NLRP3 that regulates the cellular response to a wide range of PAMPS/DAMPS. NLRP3 has been characterized primarily as an inflammasome-forming protein in response to infection and injury. The inflammasome regulates IL-1β and IL-18 maturation leading to their subsequent secretion from the immune cell. Secretion of these cytokines recruits other immune cells and factors that leads to the resolution of the initiating infection or injury. Hsp90, with its co-chaperone SGT1, was shown to be required for NLRP3 inflammasome activation via a direct protein-protein interaction. An Hsp90-SGT1 interaction was suggested to stabilize NLRP3 prior to inflammasome activation allowing the sensing of PAMPS/DAMPS; however, the mechanism, timing and sequence of events of this interaction have yet to be shown experimentally. Thus, the central hypothesis of this thesis is that Hsp90 regulates the activation of the NLRP3 inflammasome by stabilizing NLRP3 via direct protein-protein interactions. Treatment with DMAG, an Hsp90 inhibitor, blocked canonical NLRP3 function in differentiated THP-1 immune cells. However, we found no evidence that Hsp90-SGT1 was involved in protein-protein interactions with NLRP3. Instead, experiments revealed that DMAG attenuated IL1β gene transcription but did not interfere with translocation of the transcription factor, NF-kB to the nucleus. This suggests Hsp90 regulates the NLRP3 inflammasome by regulating transcription of NLRP3 inflammasome component genes. This project has revealed new insights for Hsp90 in the inflammatory response and suggests Hsp90 as a credible target for chronic inflammatory disorders. |
| نوع الوثيقة: | master thesis |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | Sparksman, S. (2020). Hsp90 Regulates the NLRP3 Inflammasome via the NF-kB Signaling Pathway (Unpublished master's thesis). University of Calgary, Calgary, AB.; http://dx.doi.org/10.11575/PRISM/37689Test; http://hdl.handle.net/1880/111814Test |
| DOI: | 10.11575/PRISM/37689 |
| الإتاحة: | https://doi.org/10.11575/PRISM/37689Test http://hdl.handle.net/1880/111814Test |
| حقوق: | University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. |
| رقم الانضمام: | edsbas.BA14D007 |
| قاعدة البيانات: | BASE |
| DOI: | 10.11575/PRISM/37689 |
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