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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL037675-23
Application #
8786091
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
1986-09-30
Project End
2017-11-30
Budget Start
2014-12-01
Budget End
2015-11-30
Support Year
23
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37240
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