BOATENG-READING · Nucleo-cytoplasmic shuttling proteins and mechano-signalling in cardiac myocytes

Nucleo-cytoplasmic shuttling proteins and mechano-signalling in cardiac myocytes

Project context and objectives The long-term goal of this project is to understand how mechanical stress in the myocardium leads to heart failure. Clinically, this can occur following a heart attack or as a result of long-term high blood pressure. Heart failure is a complex disease involving many cell types and signalling pathways; to understand this requires systematic modelling. To address this we have been using an in vitro model in which cultured neonatal myocytes are mechanically stretched to simulate the strains they experience in the heart. The project had the following objectives: 1. to determine the nature of myocyte adaptation in response to continuous or intermittent hypertrophic stimuli. Myocytes will be stimulated with cyclic stretch or with phenylephrine, either continuously for 48 hours or intermittently. Protein expression of atrial natriuretic peptide, calcium handling proteins and myofibrillar proteins will be measured as markers of adaptation; 2. to determine the expression and sub-cellular distribution of nucleo-cytoplasmic shuttling proteins Clock, Period 2, LPP and TRIP6 in neonatal rat cardiac myocytes exposed to continuous and intermittent hypertrophic stimuli; 3. to determine the function of Clock and Period 2 proteins in response to continuous and intermittent hypertrophic stimuli by blocking their nuclear cycling. Nuclear cycling is blocked by synthetic peptides containing a membrane translocating motif and the NLS for Clock or PER2. Main results This period has been very successful, particularly in relation to additional funding. Since the last reporting period I have been awarded about GBP 320 000 (EUR 400 000) from the British Heart Foundation (BHF) for two project grants to study myocardial adaptation. These new grants will allow the initial work that began on the Marie Curie grant to continue well beyond the end of the award and to allow me to fully establish independent research at the University of Reading. We are now fully settled in our new building and I have continued to receive good support from my hosts, the Schools of Biological Sciences and Pharmacy. Over the period of this grant, most of my activities have been associated with research because of my Research Councils United Kingdom (RCUK) fellowship. At the end of this grant, I can report that a majority of the objectives have been met and the research has raised new and exciting scientific questions. Some of this work will continue on grants recently awarded by the BHF. My RCUK fellowship at the University of Reading will also transition into a permanent lectureship beginning in October 2012. Additional research funding was obtained during the International Reintegration Grant funding period: 1. Research Endowment Trust Fund Studentship, Medical Research Council (MRC)/University of Reading; Award total: GBP 38 250 (EUR 51 255) for three years (1 October 2008 - 30 September 2011); Project title: Focal adhesion proteins and cardiac fibroblast function; 2. Royal Society grant; Award total: GBP 14 913 (EUR 19 983) for one year (1 September 2008 - 31 August 2009); Principle investigator: Samuel Boateng; Project title: Mechanical stimulation of heart cells as a model of heart failure in vitro; 3. British Heart Foundation project grant, reference number: PG/10/64/28520; Award total: GBP 205 947 (EUR 275 968) for three years (1 May 2011 - 30 April 2014); Principle investigator: Samuel Boateng; Project title: The mechanisms of heart failure: Mechanosensing and maladaptation in cardiac myocytes; 4. British Heart Foundation project grant, reference number: PG/10/97/28666; Award total: GPB 113 195 (EUR 151 681) for two years (1 July 2011 - 31 June 2013); Principle investigator: Samuel Boateng; Project title: Stress-induced post-transcriptional regulation of gene expression by the Exon Junction Complex in cardiac myocytes.

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