The role of cardiac myocyte apoptosis in the transition from compensated hypertrophy to dilated cardiomyopathy. (360G-Wellcome-071431_Z_03_B)

£126,107

Cardiac myocytes undergo hypertrophy in response to haemodynamic overload, an adaptation that initially maintains systolic cardiac function. Over time, however, the hypertrophied ventricle often becomes thin-walled, dilated and hypocontractile. Mechanisms that mediate this transition are poorly understood but work over the past 5 years has documented increased - yet quite low - levels of cardiac myocyte apoptosis in human hearts with dilated cardiomyopathy (0.1-0.3% vs 0.001-0.002% in controls). Moreover, Kitsis et al have demonstrated in transgenic mouse models that low levels of cardiac myocyte apoptosis (0.08-0.023%) are sufficient to generate dilated cardiomyopathy. In prior work, I investigated the role of heme oxygenase-1 in angiotensin II-induced hypertrophy and apoptosis using cultured neonatal cardiac myocytes. I now wish to continue to study the relationship between cardiac myocyte hypertrophy and apoptosis in an in vivo setting. I propose to test the importance of cardiac myocyte apoptosis in the development of overload-induced compensatory hypertrophy and the transition to cardiomyopathy in vivo. I will compare the molecular, cellular, structural and phyhsiological responses of wild type mice subjected to transthoracic aortic constriction with those of two transgenic models developed in Dr. Kitsis' lab in which cardiac myocyte apoptosis has been potently suppressed. These studies will test whether cardiac myocyte apoptosis plays a causal role in overload-induced hypertrophy and the transition to cardiomyopathy, an important clinical scenario in which the role of cardiac myocyte apoptosis is yet to be defined. Third generation pan-caspase pseudosubstrate inhibitors are currently in Phase I clinical development (Idun Pharm.) and Dr. Kitsis has successfully used one of these to attenuate ventricular dysfunction and dilatation in 2 different genetic cardiomyopathy models. I plan to also perform aortic constriction on wild-type mice and test the effect of this pharmacological agent on the trasition from hypertrophy to cardiomyopathy. Mosst of this work will be carried out in Dr. Kitsis' lab (Albert Einstein College of Medicine, NY) for the first 2½ years of this 3-year fellowship. All animal procedures will be done in Dr. Kitsis' lab and I will continue experiments with animal tissue collected from the aim 3 of the project (Caspase Inhibitor) in Cambridge.

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Grant Details

Amount Awarded 126107
Applicant Surname Foo
Approval Committee Neurosciences And Mental Health
Award Date 2006-04-03T00:00:00+00:00
Financial Year 2005/06
Grant Programme: Title Intermediate Clinical Fellowship
Internal ID 071431/Z/03/B
Lead Applicant Dr Roger Foo
Partnership Value 126107
Planned Dates: End Date 2007-07-31T00:00:00+00:00
Planned Dates: Start Date 2006-08-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region East of England
Sponsor(s) Prof Martin Bennett