Our Central Theme of this Program Project revised application continues to be to accelerate our efforts to translate the biology of the endogenous particulate guanylyl cyclase (GC) activators, the natriuretic peptides (NPs), into novel therapeutics for human cardiorenal disease highly relevant to heart failure and hypertension. This is motivated by the biology, therapeutics and diagnostics of the NPs and their GC receptors linked to 3',5'cyclic guanosine monophosphate (cGMP). Indeed, studies at the molecular or cell level, in murine or large animal models, in pharmacologic or physiologic studies in normal or humans with cardiovascular or renal disease and in recent human of NP gene variants have provided a view of a humoral system with broad beneficial pleiotropic actions. These beneficial properties of NP/GC/cGMP signaling include natriuresis, vasodilatation, positive lusitropism, inhibition of myocyte apoptosis and hypertrophy, inhibition of fibroblast proliferation and collagen synthesis, suppression of aldosterone and induction of vascular regeneration. Indeed, these cGMP-mediated properties of GC receptor activation linked to the NPs represent an unprecedented opportunity for novel drug discovery. Highlights of each Project are as follows: Project 1: Enhance cardiomyocyte function through chronic overexpression of the GC-A receptor utilizing a novel gene delivery strategy in experimental diastolic heart failure (Margaret Redfield MD - Project Leader);Project 2: Advance the development of oral delivery in humans of the designer NP CD-NP and the development of a second novel GC-A/-B activator individualized for cardiorenal disease (John C Burnett Jr., MD - Project Leader);Project 3: Establish in humans with systolic and diastolic preclinical heart failure with impaired renal function the synergistic action of optimizing the NP/PDEV/cGMP pathway with chronic PDEV inhibition with chronic novel GC-A activation (Dr. Horng Chen MD - Project Leader). Thus, this application brings together a highly collaborative team of physician-scientists with a highly translational proposal which should lead to innovative therapeutics for cardiorenal disease.

Public Health Relevance

Cardiovascular and renal disease is increasing worldwide and leads to heart failure and kidney failure. An unmet need is novel therapeutics for prevention and treatment of cardiorenal disease often occurring in the setting of hypertension, atherosclerosis and diabetes. Our proposal has high impact and significance as its translational strategies will accelerate biology to new drugs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL076611-09
Application #
8676579
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Sopko, George
Project Start
2004-04-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
9
Fiscal Year
2014
Total Cost
$1,872,916
Indirect Cost
$680,725
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Huntley, Brenda K; Sandberg, Sharon M; Heublein, Denise M et al. (2015) Pro-B-type natriuretic peptide-1-108 processing and degradation in human heart failure. Circ Heart Fail 8:89-97
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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