We now understand that CENP-F is a powerful regulator of microtubule (MT) function that controls diverse cell functions. Loss of CENP-F function in the early embryo results in minor changes in cardiac morphogenesis but fully penetrant, late adult-onset dilated cardiomyopathy (DCM). This was the first report demonstrating that disruption of any MT-associated protein causes heart disease, thus setting a novel but long predicted paradigm. Further, identification of a human family with a CENP-F mutation leading to multiple defects including the heart increases the significance of our work. Importantly, we have now discovered that loss of CENP-F function results in a hyper-stabilized MT network that is at increased risk with intervention of chemotherapeutics targeting MT function. Indeed, these drugs cause DCM in a significant subset of human cancer patients. These paradigm-setting data, our genetic models, and collective expertise uniquely position us to make ground-breaking and clinically relevant advances impacting human health. We have two integrated and major goals. Our first goal is to determine the precise role(s) of CENP-F and the MT network in specific events during cardiac development and how their loss of function subsequently leads to heart disease. These studies are essential for a mechanistic understanding of CENP-F function in development and in the etiology of DCM. Knowing that loss of CENP-F function hyper-stabilizes the MT network, a second independent yet interactive goal is to determine whether MT fragile hearts are at increased risk with chemotherapeutics: 1. only from a second hit directed specifically at MTs, 2. at even greater risk from a broader hit attacking MTs and other targets, and/or 3. at generalized risk from an off target hit that does not attack MTs. Thus, the proposed studies will provide a fundamental understanding of CENP-F/MT function in cardiogenesis and lead to concrete advances in the analysis of cardiovascular disease caused by chemotherapeutic intervention.
Heart development is a complex series of events and its disruption can lead to cardiac defects and disease. Loss of CENP-F, a microtubule-associated protein, in the embryo leads to adult onset disease and it is likely that CENP-/- hearts are susceptible to chemotherapeutics that target microtubules. Our proposed studies will determine which developmental events are disrupted with loss of CENP-F and identify strategies to prevent further problems with heart function with chemotherapeutic intervention is needed.
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