Myocardial infarction (MI) is a major cause of mortality and morbidly in the US. Patients that have suffered an MI (heart attack) are usually released from the hospital with a stable hemodynamic profile but with a dead portion of their heart (the infarct zone). After an MI there are major structural and functional remodeling of the heart that ultimately produce a dilated heart with poor contractile performance, culminating in congestive heart failure (HF). Novel therapies that reduce post MI structural and functional remodeling would reduce HF. Recent studies suggest that abnormalities in calcium (Ca) regulation within different portion of cardiac myocytes, termed microdomains, cause abnormalities in myocyte structure and function. In particular, there is evidence that the Ca signaling that induces pathological remodeling and contractile disturbances occurs within unique """"""""signaling"""""""" and """"""""excitation-contraction coupling"""""""" microdomains that contain a poorly understood class of canonical transient receptor potential (TRPC) channels. TRPC channel expression and activity are increased after MI and their activity has been linked to pathological hypertrophy and poor contractility. This project seeks to reduce excess TRPC channels activity to improve cardiac structure and function after MI.
The Specific Aims are: 1) To determine how TRPC channels interact with LTCCs and other Ca regulatory proteins within separate signaling and EC coupling microdomains to cause pathological hypertrophy and depressed contractility in cardiac disease. 2) To better characterize microdomain signaling by defining novel TRPC-LTCC partners, and 3) To determine if inhibition of TRPC activity after MI (expression of a dominant negative (dn) TRPC in transgenic mice and to begin translational studies with AAV6-dnTRPC in pigs) improves cardiac structure and function. This research will develop novel approaches to determine if reducing excess TRPC channel function after MI can improve cardiac structure and function. The projects build from fundamental discovery science to testing of novel therapeutics in a large animal model with essential human characteristics.

Public Health Relevance

Myocardial infarction (MI) resulting from ischemic heart disease is a major health problem in the US. There is a need to better understand and treat the consequences of MI. Our study explores the idea that the abnormalities in in cardiac structure and contractile function that develop after an MI are dependent on calcium entry via transient receptor potential channels. Our studies will attempt to prove this point and in so doing will develop approaches to block this Ca entry, to improve cardiac function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL119229-01A1
Application #
8760769
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Krull, Holly
Project Start
2014-09-01
Project End
2018-03-31
Budget Start
2014-09-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Temple University
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Harper, Shavonn C; Brack, Andrew; MacDonnell, Scott et al. (2016) Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects? Circ Res 118:1143-50; discussion 1150
Gross, Polina; Honnorat, Nicolas; Varol, Erdem et al. (2016) Nuquantus: Machine learning software for the characterization and quantification of cell nuclei in complex immunofluorescent tissue images. Sci Rep 6:23431
Wallner, Markus; Duran, Jason M; Mohsin, Sadia et al. (2016) Acute Catecholamine Exposure Causes Reversible Myocyte Injury Without Cardiac Regeneration. Circ Res 119:865-79
Glukhov, Alexey V; Balycheva, Marina; Sanchez-Alonso, Jose L et al. (2015) Direct Evidence for Microdomain-Specific Localization and Remodeling of Functional L-Type Calcium Channels in Rat and Human Atrial Myocytes. Circulation 132:2372-84
Correll, Robert N; Goonasekera, Sanjeewa A; van Berlo, Jop H et al. (2015) STIM1 elevation in the heart results in aberrant Ca²? handling and cardiomyopathy. J Mol Cell Cardiol 87:38-47
Makarewich, Catherine A; Zhang, Hongyu; Davis, Jennifer et al. (2014) Transient receptor potential channels contribute to pathological structural and functional remodeling after myocardial infarction. Circ Res 115:567-580