The role of Heparin-binding proteins in normal pancreas and acute pancreatitis

Nunes, Quentin ORCID: 0000-0002-7513-8595 The role of Heparin-binding proteins in normal pancreas and acute pancreatitis. PhD thesis, University of Liverpool.

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Abstract

Acute pancreatitis (AP) is a leading cause for hospitalisation and has significant quality of life implications for the patient and cost implications for the National Health Service. Although most episodes of AP are mild and self-limiting, the severe form of the disease is associated with a high mortality. In the absence of definitive treatment, management is mainly supportive. There is an urgent need to develop more effective biomarkers and drugs to manage AP. Genome-wide studies have demonstrated that proteins that bind to heparin (HBPs) form highly interconnected networks which are functionally important in health and disease. It was hypothesized that this is true in the pancreas and in AP. Testing this hypothesis, using mRNA as a proxy for protein, it was shown that HBPs constitute an important extracellular sub-proteome within the normal pancreas and in major pancreatic diseases that is likely to provide a rich repository of potential biomarkers and drug targets. Building upon this work, a proteomic analysis of HBPs in normal pancreas (NP) and in caerulein-induced mouse AP was undertaken. This has more than doubled the number of HBPs to 883, with 460 new HBPs identified. These may represent the most interconnected set of extracellular proteins and therefore with the greatest regulatory potential. Non canonical HBPs such as NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFA9, NDUFA10, NDUFA9 and NDUFA10 were identified and found to be underexpressed in AP as compared to NP. These may have potential moonlighting roles, not previously known. By virtue of being extracellular and binding to heparin, HBPs are accessible and are potential biomarkers and drug targets in AP. In addition to identifying existing biomarkers in AP such as pancreatic amylase, a number of HBPs with biomarkers potential such as HRG, CD14 and FN1 were identified and need further investigation. HBPs such as SERPINC1, VEGFA and PIP5K1C need further evaluation in drug development. These along with modified heparins, heparin mimetics and matrix therapy in AP provide exciting areas for future research.

Item Type:	Thesis (PhD)
Additional Information:	Date: 2015-01 (completed)
Subjects:	?? R1 ?? ?? RM ??
Depositing User:	Symplectic Admin
Date Deposited:	27 Aug 2015 10:04
Last Modified:	17 Dec 2022 01:34
DOI:	10.17638/02009329
URI:	https://livrepository.liverpool.ac.uk/id/eprint/2009329