Facilitation of collaboration with Professor N Rosenthal: Study of the role of IGF-1 in cell therapy for heart failure

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Post-infarction heart failure remains a major cause of human disability and death, and development of efficient cost-effective strategies is a high priority. Recent research has repeatedly indicated that skeletal myoblast transplantation is a promising strategy. However, importantly, there remain several fundamental issues to be resolved by laboratory research for the future success of this emerging treatment. These include unclear mechanisms of the therapeutic effects and insufficient graft ability. Such information is essential to define the most effective, safest protocol of the treatment and to further refine it. With support from an MRC Fellowship, I have been actively investigating these issues through studying the behaviour of grafted myoblasts in the cardiac environment at cellular, biochemical, and molecular levels. Current data from my own and other laboratories demonstrated that the ability of grafted skeletal cells to survive within the myocardium, transdifferentiate into cardiomyocytes and/or form intercellular connections with host cardiomyocytes is largely limited. This suggests an important role of the paracrine effect in the therapeutic benefits. More recent evidence obtained from our own experiments has given a rise to a strong, original hypothesis that IGF-1 is a central player in myoblast transplantation-induced paracrine effects. IGF-1 is likely to induce a variety of beneficial effects on every component of the failing myocardium including cardiomyocytes, vasculature, and ECM. IGF-1 is also known to enhance myocardial regeneration by amplifying recruitment of endogenous stem or progenitor cells. Further, enhancement of IGF-1 expression by transplanting myoblasts genetically modified to overexpress IGF-1 (cell-based IGF-1 therapy) may augment the therapeutic efficacy of myoblast transplantation. Addition of these studies, which fits very well to our previous and ongoing projects under the Fellowship, will enable my research to be more complete and provide greater understanding of cell therapy for treating heart failure. This application seeks to support for establishing collaboration with Professor Nadia Rosenthal at European Mouse Biology Laboratory, Italy, who is a leading scientist in muscle regeneration and IGF-1 research which are closely related and complementary to my research. This collaboration will greatly help with the effective, successful completion of the project. She will be able to provide valuable scientific advice and guidance, together with useful strains of transgenic animal. My expertise in heart research will, in turn, be useful for her to expand her research areas. Exchange and fusion of our expertise through the proposed collaboration will open the door to interesting new research areas.