Project Descripfion: This proposal seeks to develop a novel, cardiac specific and ulfimately translatable therapy for diastolic heart failure (DHF) based on the cardiac specific over-expression of the natriuretic pepfide receptor (guanylyl cyclase A (GCA)) via adeno-associated viral (AAV) gene delivery. We will optimize overexpression of GCA in rodent heart, demonstrate that restoration of cardiac GCA via gene delivery prevents heart failure in GCA deficient mice (mice with systemic (GCAnull) and mice with cardiac specific (CS- GCAnull) ablation of the GCA gene) and reverses heart failure in wild type mice with established DHF. These studies lay the foundation for translation to large mammal and human DHF in future studies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL076611-09
Application #
8676581
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
9
Fiscal Year
2014
Total Cost
$376,354
Indirect Cost
$134,083
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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Mohammed, Selma F; Borlaug, Barry A; McNulty, Steven et al. (2014) Resting ventricular-vascular function and exercise capacity in heart failure with preserved ejection fraction: a RELAX trial ancillary study. Circ Heart Fail 7:580-9
Mohammed, Selma F; Mirzoyev, Sultan A; Edwards, William D et al. (2014) Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail 2:113-22
Wan, Siu-Hin; Vogel, Mark W; Chen, Horng H (2014) Pre-clinical diastolic dysfunction. J Am Coll Cardiol 63:407-16
Gladden, James D; Linke, Wolfgang A; Redfield, Margaret M (2014) Heart failure with preserved ejection fraction. Pflugers Arch 466:1037-53
Pereira, Naveen L; Redfield, Margaret M; Scott, Christopher et al. (2014) A functional genetic variant (N521D) in natriuretic peptide receptor 3 is associated with diastolic dysfunction: the prevalence of asymptomatic ventricular dysfunction study. PLoS One 9:e85708
Dandamudi, Sanjay; Slusser, Joshua; Mahoney, Douglas W et al. (2014) The prevalence of diabetic cardiomyopathy: a population-based study in Olmsted County, Minnesota. J Card Fail 20:304-9
Jain, Amit K; Chen, Horng H (2014) ROSE-AHF and lessons learned. Curr Heart Fail Rep 11:260-5
Mohammed, Selma F; Hussain, Imad; AbouEzzeddine, Omar F et al. (2014) Right ventricular function in heart failure with preserved ejection fraction: a community-based study. Circulation 130:2310-20
Ichiki, Tomoko; Schirger, John A; Huntley, Brenda K et al. (2014) Cardiac fibrosis in end-stage human heart failure and the cardiac natriuretic peptide guanylyl cyclase system: regulation and therapeutic implications. J Mol Cell Cardiol 75:199-205

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