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Cardiac Death and Regeneration

Objective

Cardiac muscle death, unmatched by muscle cell creation, is the hallmark of acute myocardial infarction and chronic cardiomyopathies. The notion of heart failure as a muscle-cell deficiency disease has driven interest worldwide in ways to increase heart muscle cell number, by over-riding cell cycle constraints, suppressing cell death, or, most directly, cell grafting. Using stem cell antigen-1, we previously identified telomerase-expressing cells in adult mouse myocardium, which have salutary properties for bona fide cardiac regeneration. Here, we seek to address systematically the mechanisms for long-term self-renewal in Sca-1+ adult cardiac progenitor cells and in the smaller side population fraction, which is clonogenic and expresses telomerase at even higher levels. Specifically, we propose to study the roles of telomerase and of the telomere-capping protein, TRF2. Aim 1, Determine the properties of adult cardiac progenitor cells in mice that lack the RNA component of telomerase (TERC). Aim 2, Determine the properties of adult cardiac progenitor cells in mice that lack the catalytic component (TERT). To distinguish between effects of these two gene products themselves versus those that depend on cumulative telomere dysfunction, G2- and G5-null mice will be compared. Aim 3, Determine the properties of adult cardiac muscle and adult cardiac progenitor cells that lack the telomere-capping protein TRF2. Aim 4, Test the prediction that forced expression of TERT and TRF2 can augment cardiac muscle engraftment in vivo and enhance the clonal derivation of adult cardiac progenitor cells in vitro, without adversely affecting the cells differentiation potential. Work proposed in Aims 1-3 would provide indispensable fundamental information about the function of endogenous telomerase in adult cardiac progenitor cells. Conversely, work in Aim 4 would test potential therapeutic implications of telomerase and a telomere-capping protein with this auspicious population.

Field of science

  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /medical and health sciences/medical biotechnology/cells technologies/stem cells

Call for proposal

ERC-2008-AdG
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Address
South Kensington Campus Exhibition Road
SW7 2AZ London
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 2 497 576
Principal investigator
Michael David Schneider (Prof.)
Administrative Contact
Tatjana Palalic (Ms.)

Beneficiaries (1)

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
United Kingdom
EU contribution
€ 2 497 576
Address
South Kensington Campus Exhibition Road
SW7 2AZ London
Activity type
Higher or Secondary Education Establishments
Principal investigator
Michael David Schneider (Prof.)
Administrative Contact
Tatjana Palalic (Ms.)