. 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.
|Moynihan, Katherine L; Pooley, Ryan; Miller, Paul M et al. (2009) Murine CENP-F regulates centrosomal microtubule nucleation and interacts with Hook2 at the centrosome. Mol Biol Cell 20:4790-803|
|Pooley, Ryan D; Moynihan, Katherine L; Soukoulis, Victor et al. (2008) Murine CENPF interacts with syntaxin 4 in the regulation of vesicular transport. J Cell Sci 121:3413-21|
|Smith, T K; Hager, H A; Francis, R et al. (2008) Bves directly interacts with GEFT, and controls cell shape and movement through regulation of Rac1/Cdc42 activity. Proc Natl Acad Sci U S A 105:8298-303|
|Robertson, J Brian; Zhu, Tianli; Nasreen, Shampa et al. (2008) CMF1-Rb interaction promotes myogenesis in avian skeletal myoblasts. Dev Dyn 237:1424-33|
|Smith, Travis K; Bader, David M (2007) Signals from both sides: Control of cardiac development by the endocardium and epicardium. Semin Cell Dev Biol 18:84-9|
|Pooley, Ryan D; Reddy, Samyukta; Soukoulis, Victor et al. (2006) CytLEK1 is a regulator of plasma membrane recycling through its interaction with SNAP-25. Mol Biol Cell 17:3176-86|
|Ripley, Anna N; Osler, Megan E; Wright, Christopher V E et al. (2006) Xbves is a regulator of epithelial movement during early Xenopus laevis development. Proc Natl Acad Sci U S A 103:614-9|
|Dees, Ellen; Robertson, J Brian; Zhu, Tianli et al. (2006) Specific deletion of CMF1 nuclear localization domain causes incomplete cell cycle withdrawal and impaired differentiation in avian skeletal myoblasts. Exp Cell Res 312:3000-14|
|Osler, Megan E; Chang, Min S; Bader, David M (2005) Bves modulates epithelial integrity through an interaction at the tight junction. J Cell Sci 118:4667-78|
|Dees, Ellen; Robertson, J Brian; Ashe, Mabelle et al. (2005) LEK1 protein expression in normal and dysregulated cardiomyocyte mitosis. Anat Rec A Discov Mol Cell Evol Biol 286:823-32|
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