Heart failure is one of the leading causes of human death. The limited capacity for cardiac self-repair after muscle cell death is one of the elemental challenges in human heart disease. Calcineurin (Cn) is a calcium-regulated Serine/Threonine phosphatase involved in a wide variety of biological processes, including heart development, neuronal plasticity and lymphocyte activation.
We have recently demonstrated that expression of a naturally occurring splicing variant of the Cn catalytic subunit (termed CnAb eta1) is able to enhance skeletal muscle regeneration, reducing scar formation and inflammation.
We hypothesize that CnAbeta1 expression in adult heart results in enhanced cardiac healing capacity and propose the following research aims:
- To analyse of t he expression of the different CnA isoforms in human and mouse models of cardiac failure and regeneration
- To analyse of the effect of expressing CnAbeta1 and its alternative splicing variant CnAbeta2 in the heart
- To study the capacity of CnAbeta1 to enhance cardiac regeneration
- To identify the signalling mechanisms triggered by CnAbeta1 Myocardial over-expression of CnAbeta1 and CnAbeta2 will be examined using a cardiac-specific transgenic mouse model and by cell-based delivery methods.
Effects of C nAbeta1 on cardiac regeneration will be analysed in myocardial infarction and generalised heart failure models. The results obtained will provide key information for our understanding of the mechanisms underlying cardiac regeneration and calcineurin regulation and function, increasing the European knowledge base.
Moreover, the proposed project will evaluate the potential of CnAbeta1 as a therapeutic agent for the treatment of heart failure, allowing the generation of new clinical protocols and drugs based o n the use of this molecule and thereby contributing to increase European competitiveness.
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