Award details

Investigating the role of Bag-1 in the heart using an inducible and conditional transgenic mouse

Reference	BB/C005783/1
Principal Investigator / Supervisor	Professor Paul Townsend
Co-Investigators / Co-Supervisors
Institution	University of Southampton
Department	Human Genetics
Funding type	Research
Value (£)	261,225
Status	Completed
Type	Research Grant
Start date	01/10/2005
End date	30/06/2009
Duration	45 months

Abstract

The Bag-1 proteins play key roles in the process of apoptosis in a variety of cell types. There are at least three human isoforms, S, M and L, which are all involved, to varying degrees, in mediating cell survival. Bag-1 is an endogenous cytoprotective protein and is potentially activated by death-inducing stimuli, which in turn activate heat shock proteins and thus enhance their interaction with Bag-1. Therefore, Bag-1 can act as a cochaperone and influence the chaperone function of heat shock proteins. Although there is considerable evidence that ischaemia, reperfusion (I, R) can induce apoptosis in the heart and activate effector caspases it has not been elucidated whether certain key apoptotic modulations play a role in potentiating cardioprotection. In our recent study where Bag-1 expression was analysed in cultured cardiac cells and whole hearts we established that Bag-1 proteins are upregulated and reveal they function by relocalising within the cell following I, R injury. The mechanism of action was through complex formation with the cytoprotective heat shock proteins, at the exclusion of Raf-1, in order to offer cardioprotection. However, the fundamental role of Bag-1 within the heart is unknown. The first aim of this proposal is use tissue-specific, conditional, transgenic technology to generate inducible Bag-1S and ¿L mice in the heart. We will then be able to determine the role that Bag-1 on heart apoptosis by using Langendorff ex vivo whole hearts and measuring cellular apoptosis and biochemistry in combination with organ infarction. In addition, we have novel preliminary data demonstrating the known pro-apoptotic transcription factor, STAT-1, can be repressed by Bag-1. The second aim of this proposal is to investigate and dissect the role of this Bag-1:STAT-1 interaction within cardiac myocytes and determine their affect on apoptosis following I, R-induced injury. Following the generation of the Bag-1S and L inducible mice we will isolate neonatal andadult cardiac myocytes and correlate our in vitro results using cells from the transgenic heart. We will extend our assessment to the ex vivo, inducible Bag-1, heart using the Langendorff perfusion system to confirm Bag-1 effects upon STAT-1 expression, activation and localisation, in combination with apoptosis and survival assessment. These experiments are essential and will determine the gene function of Bag-1 in the mouse and verify in vitro findings through to the in vivo heart.

Summary

unavailable

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	Ageing
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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