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Regulators of cardiac progenitor cells: focus on cancer drug targets

Research Project
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01.01.2016
 - 31.12.2018

Increased apoptosis and premature senescence of cardiac progenitor cells (CPCs) result in impaired cardiac adaptation and enhanced susceptibility of anthracycline-exposed hearts to stressors. This may apply to targeted cancer drugs as well, given their targets are expressed in the heart and involved in the regulation of cardiac homeostasis. Fms-like tyrosine kinase 3 (Flt3) is an important drug target for solid tumor and acute myeloid leukemia treatment. We recently demonstrated that Flt3 is expressed on cardiomyocytes and CPCs, and that its activation protects against apoptosis and improves post-myocardial infarction remodeling and function in mice. Further preliminary data support the hypothesis that Flt3-signaling participates in the regulation of CPCs. In this study, we will test the hypothesis that disruption of Flt3-signaling disturbs CPC homeostasis and function and facilitates cardiac disease. We will (i) characterize the role and mechanisms of Flt3-signaling in the maintenance of the cardiac cellular homeostasis and determine the functional consequences of its disruption in the mouse heart, (ii) identify roles and molecular mechanisms of Flt3 signaling in the regulation of quiescence and in vitro proliferation and differentiation capacities of CPCs, and (iii) determine whether disruption of intrinsic Flt3 signaling facilitates cardiac disease in response to additional stressors. Relevance: Cardiomyopathy and heart failure are severe and potentially life-limiting side effects of cancer therapy. Improved understanding of the roles and molecular mechanisms of intrinsic Flt3-action in the heart is mandatory to anticipate potential cardiotoxic effects and to allow for early monitoring and interdisciplinary management of patients on Flt3-targeting therapy. Furthermore, the characterization of molecular targets of cancer therapy and their roles in the heart will help guide future cancer drug design and lead to the identification of novel therapeutic targets for the treatment of cardiomyopathy and heart failure in general.

Funding

Regulators of cardiac progenitor cells: focus on cancer drug targets

SNF Projekt (GrantsTool), 01.2016-12.2018 (36)
PI : Kuster Pfister, Gabriela.
CI : Pfister, Otmar.

Members (2)

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Gabriela Kuster Pfister

Principal Investigator
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Otmar Pfister

Co-Investigator