Characterising a novel role for LBP in angiogenesis.
Doctoral thesis, UCL (University College London).
1352627__with_copyright_material_Jay Stone_Charaterising the Novel Role of LBP in Angiogenesis redacted.pdf
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Vascular remodelling and angiogenesis are commonly associated with sight threatening diseases such as age related macular degeneration (AMD) and diabetic retinopathy. Current treatments for retinal vascular pathology are limited to inhibitors of potent growth factors such as vascular endothelial growth factor (VEGF), which despite preventing any further vascular growth cannot mend the damage already done. Vascular abnormalities are associated with late stages of disease, meaning we are treating patients too late. We must identify new, earlier therapeutic tagets to preserve vision. Gene expression profiling was performed on retinal vessels isolated from three mutant mouse strains (Curlytail, VLDLR-/- and RD1) that display retinal vascular abnormalities. Sixty-two genes were found to change in all three models. One gene which was significantly up-regulated was LBP (lipopolysaccharide binding protein). This is an acute-phase response glycoprotein, which through its binding to LPS and activation of TLR4 is involved in inflammatory signalling. We have tested the hypothesis that LBP has a novel function separate from its characterised LPS recognition. qPCR analysis of VLDLR-/- mice has shown LBP to be expressed in the neuroretina and isolated vessels. qPCR data has shown LBP to be up-regulated in VLDLR-/- mice just prior to an increase in VEGF expression and the vascular abnormalities being observed. Testing LBP affects in Matrigel, Aortic ring and Metatarsal assays revealed an increase in vessel sprouts and branching. Western blot analysis has suggested LBP can induce phosphotyrosine and phophoERK responses in a variety of cell lines and immnocytochemistry data provides evidence that this is not occuring through the well-established LBP-LPS NfkB pathway. PCR analysis of older passage HUVEC which are unresponsive to LBP has given us a candidate receptor. In conclusion, we have revealed a potential role for LBP in contributing to angiogenesis.
|Title:||Characterising a novel role for LBP in angiogenesis|
|Open access status:||An open access version is available from UCL Discovery|
|Additional information:||Third party copyright material has been removed from ethesis.|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology|
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