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Not just skin deep: circulating lipids in a “localised” disease and their role in angiogenesis

Not just skin deep: circulating lipids in a “localised” disease and their role in angiogenesis
Not just skin deep: circulating lipids in a “localised” disease and their role in angiogenesis
Psoriasis affects on average approximately 3% of the world’s population and varies widely in severity. It is thought to be an autoimmune disease as immune cells invade the dermis and epidermis resulting in hyperproliferation of keratinocytes, however no autoantigen has been found despite extensive studies. There is no cure for psoriasis however there are a number of treatments which often have side effects and are not always particularly effective. Psoriasis patients are known to have dyslipidaemia, an abnormal amount of lipids in the blood, and this predisposes them to other diseases such as cardiovascular disease and diabetes. This thesis investigates Low Density Lipoprotein (LDL) and its oxidised product oxLDL as LDL is known to be problematic in other diseases. Previous work has shown that oxidised LDL affected angiogenesis in a concentration dependent manner with lower concentrations (5µg/ml) showing a stimulatory effect and high concentrations (100µg/ml) having an inhibitory effect. This previous work has hinted that oxLDL signals through another bioactive lipid, Sphingosine-1-phosphate (S1P), and therefore the effect of S1P on migration and angiogenesis has so far been the focus of this research. S1P has previously been linked to other diseases such as cancer and atherosclerosis and due to its link with these diseases, it is therefore possible that S1P is also involved in psoriasis, potentially by protecting proliferating keratinocytes from apoptosis. It was found that like oxLDL, S1P has an inhibitory effect on both migration and angiogenesis at high concentrations (10µM), however no stimulatory effect at lower concentrations (1µM-1nM) was seen. The effect of S1P on intracellular signalling has also been studied, with results showing that S1P has concentration dependent effects on both the levels of ERK phosphorylation and increases in calcium flux. Various inhibitors have also been utilised to better understand the mechanism through which S1P exerts its effects. The inhibitors had no effect at blocking S1P directed migration, however the use of inhibitors that block the S1P receptors have shown variation in the levels of phosphorylated ERK suggesting that it is the addition of the exogenous S1P that causes this phosphorylation. This research will provide further insight into the underlying molecular mechanisms leading to the development of psoriasis which may one day lead to additional treatment to those already in place and improve the quality of life for these patients.
University of Southampton
Paterson, Jemma Alanna Jane
61d7c33a-b6f0-4d6b-9f3d-1cebc80983e1
Paterson, Jemma Alanna Jane
61d7c33a-b6f0-4d6b-9f3d-1cebc80983e1
Millar, Timothy
ec88510c-ad88-49f6-8b2d-4277c84c1958
Hunt, Alan
95a3e223-da96-40e7-b47d-27dce014e305

Paterson, Jemma Alanna Jane (2020) Not just skin deep: circulating lipids in a “localised” disease and their role in angiogenesis. Doctoral Thesis, 311pp.

Record type: Thesis (Doctoral)

Abstract

Psoriasis affects on average approximately 3% of the world’s population and varies widely in severity. It is thought to be an autoimmune disease as immune cells invade the dermis and epidermis resulting in hyperproliferation of keratinocytes, however no autoantigen has been found despite extensive studies. There is no cure for psoriasis however there are a number of treatments which often have side effects and are not always particularly effective. Psoriasis patients are known to have dyslipidaemia, an abnormal amount of lipids in the blood, and this predisposes them to other diseases such as cardiovascular disease and diabetes. This thesis investigates Low Density Lipoprotein (LDL) and its oxidised product oxLDL as LDL is known to be problematic in other diseases. Previous work has shown that oxidised LDL affected angiogenesis in a concentration dependent manner with lower concentrations (5µg/ml) showing a stimulatory effect and high concentrations (100µg/ml) having an inhibitory effect. This previous work has hinted that oxLDL signals through another bioactive lipid, Sphingosine-1-phosphate (S1P), and therefore the effect of S1P on migration and angiogenesis has so far been the focus of this research. S1P has previously been linked to other diseases such as cancer and atherosclerosis and due to its link with these diseases, it is therefore possible that S1P is also involved in psoriasis, potentially by protecting proliferating keratinocytes from apoptosis. It was found that like oxLDL, S1P has an inhibitory effect on both migration and angiogenesis at high concentrations (10µM), however no stimulatory effect at lower concentrations (1µM-1nM) was seen. The effect of S1P on intracellular signalling has also been studied, with results showing that S1P has concentration dependent effects on both the levels of ERK phosphorylation and increases in calcium flux. Various inhibitors have also been utilised to better understand the mechanism through which S1P exerts its effects. The inhibitors had no effect at blocking S1P directed migration, however the use of inhibitors that block the S1P receptors have shown variation in the levels of phosphorylated ERK suggesting that it is the addition of the exogenous S1P that causes this phosphorylation. This research will provide further insight into the underlying molecular mechanisms leading to the development of psoriasis which may one day lead to additional treatment to those already in place and improve the quality of life for these patients.

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More information

Published date: April 2020

Identifiers

Local EPrints ID: 449033
URI: http://eprints.soton.ac.uk/id/eprint/449033
PURE UUID: 9a38e225-0303-45a4-b2a4-098eb2305b1d
ORCID for Timothy Millar: ORCID iD orcid.org/0000-0002-4539-2445
ORCID for Alan Hunt: ORCID iD orcid.org/0000-0001-5938-2152

Catalogue record

Date deposited: 13 May 2021 16:41
Last modified: 17 Mar 2024 06:33

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Contributors

Author: Jemma Alanna Jane Paterson
Thesis advisor: Timothy Millar ORCID iD
Thesis advisor: Alan Hunt ORCID iD

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