Anchored Phosphatase and Transcription Factor Regulation in the Heart

  • Kapiloff, Michael S, (PI)

Project: Research project

Description

? DESCRIPTION (provided by applicant): Cardiac hypertrophy is the primary compensatory response of the heart to chronic stress. Accordingly, left ventricular hypertrophy is a major risk factor for the development of dilated cardiomyopathy and heart failure. The Ca2+/calmodulin-dependent protein phosphatase Calcineurin (CaN) is a key signaling protein regulating pathological remodeling, and manipulation of CaN activity has been proposed as a therapeutic strategy. However, classical inhibitors of CaN are immunosuppressants and have adverse side effects, making this drug option unfeasible for long-term treatment of cardiac disease. We propose that targeting specific microdomains of CaN via disrupting CaN localization will open up new avenues of drug design for the treatment of hypertrophy. In particular, we have shown that the scaffolding protein mAKAP? binds both CaN and its downstream substrate MEF2D, hence creating a microdomain of CaN signaling. Additionally, mAKAP? expression is required in vivo for the induction of pathological remodeling in response to pressure overload. Our central hypothesis states that specific pools of CaN confined to select intracellular compartments such as that organized by mAKAP? provides the molecular basis for both localized activation and definition of substrate. Our three specific aims will test whether mAKAP?-bound CaN is regulated by a perinuclear Ca2+ compartment (Aim 1) that controls MEF2D gene transcription (Aim 2) and that may be selectively targeted for drug therapy for heart failure (Aim 3).
StatusActive
Effective start/end date2/1/161/31/20

Funding

  • National Institutes of Health: $403,012.00

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Calcineurin
Phosphoric Monoester Hydrolases
Transcription Factors
Heart Failure
Drug Design
Phosphoprotein Phosphatases
Dilated Cardiomyopathy
Cardiomegaly
Left Ventricular Hypertrophy
Calmodulin
Immunosuppressive Agents
Drug-Related Side Effects and Adverse Reactions
Hypertrophy
Heart Diseases
Proteins
Therapeutics
Pressure
Drug Therapy