Project description
Stimulated tissue regeneration could provide a 'cure' for a heart attack where there was none
Heart attack, scientifically referred to as myocardial infarction, is primarily due to a sudden deprivation of blood supply to the heart muscle. The tissue, deprived of oxygen and nutrients, becomes necrotic and forms scar tissue over several weeks. The lasting damage can weaken the heart and impair its ability to effectively pump blood. The EU-funded CuRE project is seeking a revolutionary breakthrough in treatment of this increasingly prevalent condition, namely therapy that stimulates regeneration of functioning cardiac cells. Beginning with libraries of factors that may do so, the team will use a combination of in vitro and in vivo testing leading to identification of the most effective ones and development of a suitable therapy relying on them.
Objective
Biotechnological therapies for patients with myocardial infarction and heart failure are urgently needed, in light of the breadth of these diseases and a lack of curative treatments. CuRE is an ambitious project aimed at identifying novel factors (cytokines, growth factors, microRNAs) that promote cardiomyocyte proliferation and can thus be transformed into innovative therapeutics to stimulate cardiac regeneration. The Project leads from two concepts: first, that cardiac regeneration can be obtained by stimulating the endogenous capacity of cardiomyocytes to proliferate, second that effective biotherapeutics might be identified through systematic screenings both in vivo and ex vivo. In the mouse, CuRE will take advantage of two unique arrayed libraries cloned in adeno-associated virus (AAV) vectors, one corresponding to the secretome (1200 factors) and the other to the miRNAome (800 pri-miRNA genes). Both libraries will be functionally screened in mice to search for factors that enhance cardiac regeneration. This in vivo selection approach will be complemented by a series of high throughput screenings on primary cardiomyocytes ex vivo, aimed at systematically assessing the involvement of all components of the ubiquitin/proteasome pathway, the cytoskeleton and the sarcomere on cell proliferation. Cytokines and miRNAs can both be developed to become therapeutic molecules, in the form of recombinant proteins and synthetic nucleic acids, respectively. Therefore, a key aim of CuRE will be to establish procedures for their production and administration in vivo, and to assess their efficacy in both small and large animal models of myocardial damage. In addition to this translational goal, the project will entail the successful achievement of several intermediate objectives, each of which possesses intrinsic validity in terms of basic discovery and is thus expected to extend technology and knowledge in the cardiovascular field beyond state-of-the art.
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Funding Scheme
ERC-ADG - Advanced GrantHost institution
WC2R 2LS London
United Kingdom