The heart consumes tremendous amounts of energy. Loss of normal energy homeostasis is a hallmark of cardiac failure. The nuclear receptor co-activator PPAR-Gamma Co-activator 1 (PGC1)-alpha is a well-established global regulator of energy homeostasis in numerous tissues; strong evidence suggests that it does so in the heart as well. Evidence also points to modulation of PGC1-alpha in heart failure, coincident with important changes in energy homeostasis. PGC1-beta, a close homologue of PGC1-alpha, has closely overlapping functions and is equally abundant in the heart, yet no definitive demonstration of its role in normal or diseases heart has been made. The precise mechanisms whereby PGC1-alpha and beta act in the heart remain poorly understood. Here, we hypothesize that PGC1-alpha and -beta play essential roles in regulating the heart's ability to meet energy demands. To address this hypothesis, the metabolic and contractile functions of hearts from mice deficient for either PGC1-alpha or beta will be investigated. Genetic expression in these hearts will also be studied in search of better insight into the mechanisms of PGC1-alpha and beta in this tissue. We also hypothesize that down-regulation of PGC1-alpha is a maladaptive response that contributes to the development of heart failure. To address this question, we will determine if preventing down-regulation of PGC1-alpha can prevent heart failure. The ultimate goals of this project are twofold: first, to help decipher the molecular mechanisms that control metabolism and contractile function in normal and diseased hearts; and second, to transition the applicant to an independent career of investigation in cardiac physiology and transcriptional mechanisms using genetic manipulations of mice as a tool.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL079172-03
Application #
7171864
Study Section
Special Emphasis Panel (ZHL1-CSR-M (O1))
Program Officer
Scott, Jane
Project Start
2005-02-01
Project End
2007-12-31
Budget Start
2007-02-01
Budget End
2007-12-31
Support Year
3
Fiscal Year
2007
Total Cost
$130,962
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Rowe, Glenn C; Jiang, Aihua; Arany, Zolt (2010) PGC-1 coactivators in cardiac development and disease. Circ Res 107:825-38
Gupta, Rana K; Arany, Zoltan; Seale, Patrick et al. (2010) Transcriptional control of preadipocyte determination by Zfp423. Nature 464:619-23
Arany, Zoltan; Wagner, Bridget K; Ma, Yanhong et al. (2008) Gene expression-based screening identifies microtubule inhibitors as inducers of PGC-1alpha and oxidative phosphorylation. Proc Natl Acad Sci U S A 105:4721-6
Arany, Zolt (2008) PGC-1 coactivators and skeletal muscle adaptations in health and disease. Curr Opin Genet Dev 18:426-34
Arany, Zoltan; Lebrasseur, Nathan; Morris, Carl et al. (2007) The transcriptional coactivator PGC-1beta drives the formation of oxidative type IIX fibers in skeletal muscle. Cell Metab 5:35-46
Arany, Zoltan; Novikov, Mikhail; Chin, Sherry et al. (2006) Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-gamma coactivator 1alpha. Proc Natl Acad Sci U S A 103:10086-91