Chemokines are chemotactic cytokines, which mediate cell trafficking and play a key
role in mobilisation of leukocytes. More recently, chemokines and their cognate
receptors have been described as key players in different aspects of cancer biology
contributing to proliferation, angiogenesis and metastasis. In particular, chemokines
CCL19 and CCL21 acting on their associated receptor CCR7 are postulated to be key
drivers of lymph node metastasis in a number of malignancies including breast, colon,
gastric, & thyroid cancers. It has been reported that the cleavage of the pre-cysteine
bridge N-terminal residues of CCL21 (SDGGAQD) and of CCL19 (GTNDAED) renders
both peptides incapable of fully activating CCR7. However, little is known about the
nature of the interactions that occur between the N-terminal residues of CCL19 or
CCL21 and the CCR7 receptor, or the role they have in activation of CCR7. The aim
of this study is to investigate the role of the residues in the N-terminus of CCL19 and
in particular CCL21 in the context of CCR7 activation and to use this information in the
discovery of novel CCR7 antagonists or agonists. To achieve this, we synthesised a
number of short (three to seven amino acids) peptides and peptidomimetics inspired
by the seven N-terminal amino acid residues of CCL19 and CCL21 and
pharmacologically characterised their ability to activate CCR7 or block the activation
of CCR7 using a number of in vitro assays such as calcium flux, trans-well (Boyden
chamber), and Western blotting. We also carried out computational studies to better
understand and predict the activity of these peptides. Our results demonstrate that
some of these peptides are indeed capable of acting as agonists or antagonists of
CCR7. / Kuwait Health Ministry and Kuwait Civil Services Commission
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/19699 |
| Date | January 2021 |
| Creators | Alotaibi, Mashael A.F.J. |
| Contributors | Afarinkia, Kamyar |
| Publisher | University of Bradford, Institute of Cancer Therapeutics. Faculty of Life Science |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Thesis, doctoral, PhD |
| Rights | <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. |
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