The main goal of this project is a preclinical trial of a potential new drug to treat heart failure (HF), dabuzalgron, a highly selective alpha-1A-adrenergic receptor (a1A-AR) partial agonist drug. Dabuzalgron is not approved for use in patients, but had no toxicity in Phase 2 trials for a different indication, so has a viable path to clinical use. HF is a major problem, but few new drugs have resulted from 30 years of basic research. This project is based on the novel idea that cardiac myocyte a1A-ARs are an endogenous adaptive signaling system that protects and repairs myocytes after injury, via ERK activation. The catecholamines norepinephrine (NE) and epinephrine (EPI) activate two types of ARs on cardiac myocytes, the dominant beta- ARs, which increase heart contraction, and a1-ARs, which are few in number and studied much less. In HF, when NE and EPI are high, beta-AR stimulation can be damaging, so beta-AR-blockers are class I therapy. a1-ARs are relatively unoccupied in HF, and an exogenous a1A agonist can be therapeutic. Indeed, 2 different selective a1A agonists, dabuzalgron and A61603, treat HF in several mouse models, via pleiotropic cellular and signaling mechanisms, including changes in hypertrophy, less myocyte death, improved metabolism, reduced fibrosis, and increased contractile proteins, via ERK as a central mechanism. The a1A-ERK mechanism is preserved in human myocardium. These beneficial effects are seen at dosing far below that which increases blood pressure, the recognized role of alpha-1-ARs. This project will take several key steps toward translation. First, unlike A61603, dabuzalgron has been studied in patients, so the path to a clinical drug is feasible. Second, unlike A61603, dabuzalgron dosing is such that assay of drug levels at therapeutic dosing is possible. Third, dabuzalgron will be used in a mouse model of chronic post-MI HF, a type of HF that could be a first clinical trial in patients. Fourth, females will be studied, in addition to males. Finally, the project will test a novel mechanism of action for HF drugs, stimulating protective growth factors from myocytes, and/or from brown adipose tissue. The overall hypothesis is that an alpha-1A agonist that has been used in patients can rescue cardiac function in a mouse model of chronic post-MI HF, and one mechanism is increased protective growth factors. There will be 2 aims, one translational and one more mechanistic.
Aim I : Test whether dabuzalgron can rescue cardiac function in a mouse model of post-MI HF.
Aim II : Test whether a1A agonism works by stimulating growth factors from cardiac myocytes and/or brown adipocytes. Successful completion of these Aims will provide preclinical validation of a potential novel HF drug with a unique mechanism of action as an agonist. This mechanism contrasts with current class I HF drugs, which are all antagonists, and which all have the therapy-limiting side effect of low blood pressure.
Heart failure, which leads to trouble breathing and fatigue, is one of the most common, serious medical problems in the United States. It has caused about 1 million hospital admissions each year since 1997, and is fatal in 20% of patients within 1 year of diagnosis. A 40-year old man or woman has a 20% chance of developing heart failure. Despite these serious statistics, few new drugs for heart failure have been proved for many years. The goal of this project is to validate a potential new drug to treat heart failure. Successful completion of the project will accelerate the process of heart failure drug development.
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