Investigation into the role of inositol 1,4,5-triphosphate mediated calcium release in controlling cardiac hypertrophy

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

Heart disease is a significant cause of mortality in the developed world. In 2004 it was responsible for 137,700 deaths in the UK, equating to 24 percent of all deaths. A major predictor of mortality due to heart disease is cardiac hypertrophy (an increase in cell size without increase in cell number), and it is the most important risk factor for heart failure in humans. Hypertrophy can however also be a beneficial adaptive response providing the increased blood supply required during pregnancy and to sustain levels of increased physical activity experienced by athletes. Cardiac hypertrophy is characterised by an increase in the muscle mass/size of the heart due to enlargement of heart cells without any proliferation. Calcium increases in the muscle cells of the heart control contraction and the activity of genes that determine heart size. Since during disease the heart can grow too much, causing it not to work so well and fail, it is important to understand how calcium can precisely regulate the genes' activity and heart contraction. Using microsocopy and molecular biology techniques, we will measure changes in cell calcium and gene activity associated with heart growth. The effect of modifying calcium changes upon heart growth will also be monitored. Using these approaches, we aim to understand how calcium can precisely control myocyte (muscle cell) transcription (the copying of DNA information into RNA) independent of its effects on contraction. Ultimately, drugs will be developed to control heart growth without affecting heart function.

Publications

10 25 50
 
Description That nuclear localised increases in calcium could be interpreted by the cardiac myocyte separate from the increase in calcium that control contraction to induce cardiac growth.
We also found that these calcium changes coming from IP3 receptor channels could act to alter the amount of IP3 receptors. This not being by switching on the gene but by controlling a small RNA called a microRNA that could regulate how much protein was made from the IP3R mRNA.
Exploitation Route By identifying some of the mechanism by which gene expression required for the cardiac growth during disease is controlled, we have found a new way to treat heart disease.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description Odysseus FWO
Amount € 837,974 (EUR)
Funding ID 90663 
Organisation Research Foundation - Flanders (FWO) 
Sector Charity/Non Profit
Country Belgium
Start 10/2014 
End 09/2019
 
Description Project Grant
Amount € 472,485 (EUR)
Funding ID G08861N 
Organisation Research Foundation - Flanders (FWO) 
Sector Charity/Non Profit
Country Belgium
Start 01/2016 
End 12/2019
 
Description Catalucci 
Organisation Institute of Genetic and Biomedical Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of effect of micro RNA on heart growth
Collaborator Contribution Provision of hearts from mice injected with miRNA inhibitor.
Impact 23166348
Start Year 2011
 
Description Conway 
Organisation University of Oxford
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution USe and testing of cell permeant IP3 analogues
Collaborator Contribution Provision of Cell permeant IP3 analogues
Impact 23166348 20106523 19934645 19549843 19250908 18407350 18250332 17692540 17585817 17574672 16882691 16814379 15561771 15263017 14685260 12767897
 
Description MIkoshiba 
Organisation RIKEN
Department RIKEN Brain Science Institute
Country Japan 
Sector Public 
PI Contribution Analysis of tissue from itpr2 KO animals Use of IP3R2 monoclonal Antibody
Collaborator Contribution Provision of IP3R2 monoclonal antibody. Provision of heart tissue from IP3R2 KO animals
Impact Publication in JCB: 23166348 Publication in Mol Cell: 19250908
 
Description Molkentin 
Organisation Cincinnati Children's Hospital Medical Center
Department Department of Pediatrics
Country United States 
Sector Academic/University 
PI Contribution Analysed the mice
Collaborator Contribution The collaborator provided hearts from control and aortically constricted mice transgenic for the IP3R Ligand binding domain and for type 2 IP3 receptors.
Impact Publication in Journal of Cell Biology in 2012 23166348
Start Year 2011
 
Description Norway Rats 
Organisation University of Oslo
Department Institute for Experimental Medical Research
Country Norway 
Sector Academic/University 
PI Contribution Analysis of Cardiac Myocyte proteome, transcriptome and epigenome.
Collaborator Contribution Provision and phenotyping of hearts hypertrophic due to exercise, aortic banding or ageing.
Impact Publication in JCB in 2012 27893464 23166348
Start Year 2009
 
Description Ritter 
Organisation University of Wurzburg
Country Germany 
Sector Academic/University 
PI Contribution Analysis of Cardiac tissue from aortically constricted mice. Analysis of effect of cell permeant peptide that prevents calcineurin nuclear import upon NFAT accumulation in the nucleus.
Collaborator Contribution Provision of tissue from surgically prepared mice. Provision of cell permeant peptide. Provision of GFP-tagged calcineurin expression vectors.
Impact Publication in Mol Cell: 19250908 Publication in PNAS: 19549843
Start Year 2007
 
Description UT SW 
Organisation University of Texas Southwestern Medical Center
Country United States 
Sector Academic/University 
PI Contribution Analysis of Tissue from miR-133 DKO animals
Collaborator Contribution Provision of tissue and mRNA from miR-133 double knockout animals
Impact Publication in JCB in 2012: 23166348
Start Year 2010
 
Description 2. September 2013. Cambridge-Yale Cardiovascular Meeting, Yale, USA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Interacted with clinicians and scientists from Yale and Cambridge
50 attendees at meeting.


Useful interactions made that may progress to formal collaborations.
Year(s) Of Engagement Activity 2013
 
Description 3. June 2013. Calcium Signalling Gordon Research Conference. Il Ciocco. Italy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 200 Participants.

Valuable interactions subsequent
Year(s) Of Engagement Activity 2013
 
Description Heart Failure 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Heart Failure 2012, April 2012, Belgrade
http://www.escardio.org/congresses/hf2012/pages/welcome.aspx
Oral Presentation
Abstract title: IP3 induced calcium release engages a pro-hypertrophic autoamplifying loop that relieves miR-133a mediated suppression of IP3RII
Authors: FM Drawnel, D Wachten, JD Molkentin, I Sjaastad, N Liu, MD Bootman and HL Roderick.

The data was discussed and new directions for the research considered.
Year(s) Of Engagement Activity 2012
 
Description Invited Speaker - Biochemical Society meeting 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk provoked interest and discussions.


Possible collaborations initiated
Year(s) Of Engagement Activity 2014