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Title: Identifying the causes and cellular effects of focal segmental glomerulosclerosis (FSGS)
Author: Harris, Jessica Jean
ISNI:       0000 0004 2718 6677
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2011
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In focal segmental glomerulosclerosis (FSGS) the cleaning of blood via filtration is disrupted and ultimately this disease results in the destruction of the kidney, the need for patient dialysis and eventually a kidney transplant. Unfortunately this disease can come back after transplantation affecting the new kidney; this has lead to the hypotheses that there is either something missing from the blood that is essential for healthy kidney maintenance or something present in the blood that is damaging the kidney. Patients, who relapse, after kidney transplantation, can go in to remission when plasma exchange is carried out. The podocyte is the target of disease in FSGS; it undergoes dramatic structural changes and eventually comes away from the glomerular basement membrane. However little is known about what causes these changes. The aim of this project is to deduce what factors in/or missing from plasma are causing these changes and the pathways through which they are working. Using plasma exchange material, collected from patients in nephrotic and non-nephrotic stages of disease, the effects of FSGS plasma on human conditionally immortalised podocytes (ciPods) have been studied. Actin associated protein vasodilator stimulated phosphoprotein (VASP) is located at the end of stress fibres in podocytes and is phosphorylated in response to nephrotic plasma at Ser157 and Ser239. This phosphorylation is carried out by protein kinase A (PKA). VASP phosphorylation can be blocked by the inhibition of proteases in the plasma and siRNA knockdown of protease activated receptor 1 (PAR1). An antibody microarray carried out by KINEXUS bioinformatics indicated a role for calcium signalling in response to nephrotic plasma. These findings indicate that the actin cytoskeleton is affected by nephrotic plasma and support the hypothesis that a circulating protease may be involved in the pathology of FSGS. Greater understanding of these proteases and the signalling pathways activated in disease may lead to novel therapeutic targets.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available