Heart failure (HF) affects an estimated 4.7 million Americans, with approximately 550,000 new cases diagnosed annually and estimated annual costs ranging from $10 to $40 billion. One of the characteristics of progression to heart failure is reduced cardiac output due to decreased contractility and cardiac hypertrophy. We have identified a novel a cAMP-dependent pathway, involving the novel cAMP binding protein, Epac, and PLCe that increases cardiac calcium-induced calcium release (CICR) and ionotropic responses to ?-adrenergic receptor (BAR) stimulation. This pathway functions in physiological regulation of cardiac function and may also contribute to increased diastolic calcium release that underlies arrhythmogenesis during chronic adrenergic receptor stimulation. We will expand on this published discovery of a new PLCe dependent regulatory pathway in the heart by following new clues from our new exciting preliminary data on the importance of PLCe sub cellular scaffolding and signaling in regulation of both CICR and hypertrophy. The major focus is on I. understanding mechanisms underlying how sub cellular scaffolding of PLC5e may specify contractile vs. hypertrophic signaling, and II. Examining how PLCe can potentially integrate inputs from multiple signaling pathways by virtue of its unique ability to respond to multiple molecular signals. We will achieve these goals by exploring the following hypotheses: 1) Scaffolding to the Type II Ryanodine receptor (RyR2) and muscle A kinase anchoring protein (mAKAP) specifies distinct compartmentation of PLCe in cardiac cells. We found that PLCe forms complexes with both mAKAP and RyR2 in the heart. We hypothesize that mAKAP- and RyR2-complexed PLCe are separately compartmentalized pools in cardiac myocytes involved in regulation of hypertrophy and CICR, respectively. To address this idea we will examine the nature of the scaffold PLCe complexes and determine the roles of these complexes in cardiac function 2) Role of PLCe scaffolding in regulating hypertrophic signaling at the nucleus. We will explore the hypothesis developed in aim 1 that scaffolding PLCe in the heart specifies regulation of distinct functional Ca2+ signals involved in CICR in the SR, and inositol trisphosphate (IP3) dependent Ca2+ signals in the nucleus. We will also examine the role of scaffold PLCe in local diacylglycerol (DAG), PKC and PKD signals at the nucleus. We will also examine how PLCe can integrate multiple upstream signals to regulate these processes. 3) Mechanisms for PLCe- dependent regulation of cardiac hypertrophy. Preliminary data indicate that siRNA-dependent knockdown of PLCe inhibits protein synthesis stimulated by chronic ET-1 and Iso treatment in neonatal rat ventricular myocytes (NRVMs) suggesting PLCe involvement in cardiac hypertrophy, a marker for development of heart failure. We will explore these mechanisms further in a whole animal model system with cardiac myocyte specific deletion of PLCe.

Public Health Relevance

: Heart failure (HF) affects an estimated 4.7 million Americans, with approximately 550,000 new cases diagnosed annually and estimated annual costs ranging from $10 to $40 billion. One of the characteristics of progression to heart failure is reduced cardiac output due to decreased contractility and cardiac hypertrophy. The proposed experiments to understand new roles for phospholipase C in the heart will address fundamental mechanisms of heart failure and function that could lead to the development of novel therapies for heart failure.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM053536-14S2
Application #
8651148
Study Section
Program Officer
Dunsmore, Sarah
Project Start
1996-09-30
Project End
2015-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
14
Fiscal Year
2013
Total Cost
$25,085
Indirect Cost
$8,743
Name
University of Rochester
Department
Pharmacology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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