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You searched for +publisher:"University of Manchester" +contributor:("Gieling, Roben"). Showing records 1 – 2 of 2 total matches.

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University of Manchester

1. Likhatcheva, Maria. DISSECTION OF THE FACTORS INVOLVED IN CHROMATIN REMODELLING AND DNA DAMAGE RESPONSE PATHWAY IN HYPOXIC CONDITIONS.

Degree: 2018, University of Manchester

Hypoxia, a common feature of solid tumours, is associated with poor prognosis, a more aggressive tumour phenotype and therapeutic resistance. Tumour hypoxia induces changes in the chromatin structure, with induction of the heterochromatin mark H3K9me3 frequently observed. The upregulation of H3K9me3 was observed with co-incidental upregulation of the methyltransferase Suv39H1 in three (FTC133, U87 and HCT116) different cancer cell lines exposed to hypoxic conditions (0.1% O2). Thus, it was hypothesised that Suv39H1 was a candidate for the tri- methylation of H3K9 and the first part of this study was focused on investigating the potential regulatory mechanisms. RT-qPCR analysis showed no changes in the levels of Suv39H1 mRNA in hypoxia suggesting a post transcriptional regulation mechanism. In mild hypoxic conditions (O2 ≥1%) the cells failed to induce H3K9me3 and Suv39H1. However, treatment with proteasome inhibitor MG132 in mild hypoxia induced Suv39H1 upregulation, suggesting the involvement of the proteasomal pathway in the regulation of Suv39H1 stability in hypoxia. Under normal oxygen conditions Suv39H1 is degraded via MDM2 dependent ubiquitination, which is blocked by the protein Sirt1. However, the levels of Sirt1 were highly downregulated and MDM2 protein levels were maintained following hypoxic exposure. It has been previously reported that ATM is activated in response to hypoxia and negatively regulates MDM2 activity in response to DNA damage. To test the involvement of ATM and MDM2 in regulating Suv39H1 levels in hypoxia, the ATM specific inhibitor (Ku55933) was used together with MDM2 knockdown under normal oxygen conditions and hypoxia. As predicted, highest levels of Suv39H1 were observed when ATM is catalytically active (hypoxia) and MDM2 inactive (knockdown). The results of this study indicate an important role that ATM has in regulating chromatin structure in response to stress conditions, such as hypoxia, through regulation of MDM2. As ATM plays a crucial role in the hypoxia induced DNA damage response, the second part of this study was focused on uncovering ATM activation in hypoxia. It has been previously reported that the acetyltransferase Tip60 is involved in ATM activation in response to DNA damage. However, if Tip60 plays a role in the hypoxia induced activation of ATM hasn’t been tested to date. In order to do this a Tip60 specific inhibitor, TH1834, was used. FTC133 and HCT116 cells were treated with TH1834 under hypoxic conditions and the levels of the catalytically active form of ATM were assessed by Western blot and IF. The obtained results showed a clear involvement of Tip60 in the hypoxia induced activation of ATM. Finally, as the activation of ATM in hypoxia has been related to S-phase arrest, the cell cycle distribution of FTC133 and HCT116 cells were analysed by FACS. The result showed that ATM activation in FTC133 cells seems independent of S-phase arrest. Heterochromatin is suggested to be important for cancer cell survival. This study proposes that ATM is involved in… Advisors/Committee Members: DEMONACOS, CONSTANTINOS C, GIELING, ROBEN R, Williams, Kaye, Demonacos, Constantinos, Gieling, Roben.

Subjects/Keywords: Hypoxia ATM Suv39H1

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

APA (6th Edition):

Likhatcheva, M. (2018). DISSECTION OF THE FACTORS INVOLVED IN CHROMATIN REMODELLING AND DNA DAMAGE RESPONSE PATHWAY IN HYPOXIC CONDITIONS. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317434

Chicago Manual of Style (16th Edition):

Likhatcheva, Maria. “DISSECTION OF THE FACTORS INVOLVED IN CHROMATIN REMODELLING AND DNA DAMAGE RESPONSE PATHWAY IN HYPOXIC CONDITIONS.” 2018. Doctoral Dissertation, University of Manchester. Accessed January 19, 2021. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317434.

MLA Handbook (7th Edition):

Likhatcheva, Maria. “DISSECTION OF THE FACTORS INVOLVED IN CHROMATIN REMODELLING AND DNA DAMAGE RESPONSE PATHWAY IN HYPOXIC CONDITIONS.” 2018. Web. 19 Jan 2021.

Vancouver:

Likhatcheva M. DISSECTION OF THE FACTORS INVOLVED IN CHROMATIN REMODELLING AND DNA DAMAGE RESPONSE PATHWAY IN HYPOXIC CONDITIONS. [Internet] [Doctoral dissertation]. University of Manchester; 2018. [cited 2021 Jan 19]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317434.

Council of Science Editors:

Likhatcheva M. DISSECTION OF THE FACTORS INVOLVED IN CHROMATIN REMODELLING AND DNA DAMAGE RESPONSE PATHWAY IN HYPOXIC CONDITIONS. [Doctoral Dissertation]. University of Manchester; 2018. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317434


University of Manchester

2. Spadea, Alice. HYALURONIC ACID BASED NANOPARTICLES FOR SPECIFIC TUMOUR TARGETING.

Degree: 2018, University of Manchester

Two of the main limitations of conventional cancer drugs are their lack of ability to discriminate between cancer and normal cells, producing the well-known side effects, and the resistance to radio- and chemotherapy. The resistance is mainly due to the presence of hypoxic (low oxygen) regions in tumours where the Hypoxia Inducible Factor (HIF) transcriptional system regulates the expression of hypoxia-dependent pro-survival and drug resistance genes. The development of a delivery system capable of specifically targeting and penetrating tumours is a promising strategy to overcome these issues. Currently, one of the most investigated agents for cancer targeting is hyaluronic acid (HA), since its main receptor, CD44, is overexpressed in many cancers. However, it is still unclear which cell-related factors influence HA binding and internalisation (collectively called “uptakeâ€) into CD44 expressing cells. To address this, the expression of CD44 (standard and variants isoforms, CD44s and CD44v respectively) was evaluated in human dermal fibroblasts (HDF) as healthy control and in a large panel of cancer cell lines. It was found that the expression of CD44v can negatively influence the uptake of HA but, interestingly, the healthy control HDF that expressed high levels of CD44s were less efficient in taking up HA when compared to high expressing CD44s cancer cells. Starting from this knowledge, HA-coated chitosan (CS)-based nanoparticles (NPs), engineered to contain siRNAs to knockdown HIF-1, were used to target CD44s expressing pancreatic cancer cell lines (MIA PaCa-2 and PANC-1). Two different NPs were formulated using low or high molecular weight (LMW or HMW) CS evaluating differences in their internalisation by cells and correlating that with gene silencing studies. Cells showed a slower internalisation of HMW CS/HA NPs compared to the LMW counterpart. However, the latter were slightly more efficient in HIF-1α and its downstream target genes knockdown. LMW CS/HA NPs were able to penetrate deeply into multicellular spheroids, but when injected intravenously in tumour bearing mice they resulted not completely stable (with potential decomplexation) as 48 hours post-injection most of HA was detected in the liver and the siRNA in the kidneys. In conclusion, these results provide some understanding on the interplay between CD44 expression, its functionality and the underlying mechanism(s) for HA uptake and importantly, demonstrate that factors other than the amount of CD44 receptor can play a role in the interaction with HA. However, other methods for preparation or in vivo administration of HA/CS NPs need to be evaluated to assess the system stability in a route different from intravenous. Advisors/Committee Members: WILLIAMS, KAYE KJ, GIELING, ROBEN R, Stratford, Ian, Williams, Kaye, Gieling, Roben.

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

APA (6th Edition):

Spadea, A. (2018). HYALURONIC ACID BASED NANOPARTICLES FOR SPECIFIC TUMOUR TARGETING. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317733

Chicago Manual of Style (16th Edition):

Spadea, Alice. “HYALURONIC ACID BASED NANOPARTICLES FOR SPECIFIC TUMOUR TARGETING.” 2018. Doctoral Dissertation, University of Manchester. Accessed January 19, 2021. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317733.

MLA Handbook (7th Edition):

Spadea, Alice. “HYALURONIC ACID BASED NANOPARTICLES FOR SPECIFIC TUMOUR TARGETING.” 2018. Web. 19 Jan 2021.

Vancouver:

Spadea A. HYALURONIC ACID BASED NANOPARTICLES FOR SPECIFIC TUMOUR TARGETING. [Internet] [Doctoral dissertation]. University of Manchester; 2018. [cited 2021 Jan 19]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317733.

Council of Science Editors:

Spadea A. HYALURONIC ACID BASED NANOPARTICLES FOR SPECIFIC TUMOUR TARGETING. [Doctoral Dissertation]. University of Manchester; 2018. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317733

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