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Effects of resistin on platelet function and its receptor, adenylyl cyclase associated protein 1

Joshi, Pooja Laxmikant (2017) Effects of resistin on platelet function and its receptor, adenylyl cyclase associated protein 1. PhD thesis, University of York.

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Abstract

Resistin is an adipokine which is found elevated in patients suffering from metabolic syndrome, affecting a large proportion of the population. It is characterised by obesity, insulin resistance (IR), type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD), which are the biggest contributors to morbidity and mortality in the modern world. Platelets play a major role in CVD, where their activation leads to formation of thrombi, which when uncontrolled, leads to the pathophysiological effects of CVD. The role of resistin in CVD progression and its mechanism of action on its target cells still remains debatable and surrounded by controversies. In a bid to assess this, the present study aims at illustrating the effect of resistin on platelet activation by deriving conclusions from platelet functional assays. This thesis makes novel observations that resistin blunts thrombin-mediated platelet aggregation and secretion and seemingly affects the platelet actin cytoskeleton. It also finds that resistin activates downstream effectors of phosphoinositide 3 kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways in platelets. Adenylyl cyclase associated protein 1 (CAP1), a cytoskeletal protein, was recently identified as a receptor for resistin. When CAP1 was investigated in platelets, interesting observations were made, where CAP1 temporally translocated from the membrane fraction in response to thrombin mediated activation. Furthermore, in an attempt to improve our knowledge of platelet biology and to delineate future avenues for exploration, an observational proteomics investigation of cytoskeletal proteins and the change in abundance upon thrombin activation was carried out, further highlighting their importance in platelet regulation. Additionally the subcellular localisation of specific cytoskeletal proteins (IQGAP1, Arp2/3, coronin1a, profilin, cofilin, villin, l-plastin, myosin IIa, and tropomyosin) that are either known or hypothesised to interact with CAP1 was also conducted. Further investigations with proteins IQGAP1 and Arp2/3 revealed that these proteins did not interact with CAP1.

Item Type: Thesis (PhD)
Academic Units: The University of York > Hull York Medical School (York)
Depositing User: Ms Pooja Laxmikant Joshi
Date Deposited: 14 Nov 2017 16:23
Last Modified: 18 Oct 2018 00:18
URI: http://etheses.whiterose.ac.uk/id/eprint/18450

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