Abstract

Postoperative atrial fibrillation (poAF) is a common complication of cardiothoracic surgery with an incidence between 10 and 50%. This condition typically peaks on day 2-3 following surgery. Very little remains known about the molecular mechanisms underlying poA, which makes the development of better therapies difficult. Our preliminary results suggest that patients and mice with reduced levels of ?Striated Muscle Preferentially Expressed Protein Kinase? (SPEG) in the atria have an increased risk of developing poAF. The overall goal of this project is to elucidate the molecular and cellular mechanisms by which reduced SPEG levels cause altered intracellular Ca2+ handling and poAF. Juwan will test the hypothesis that reduced SPEG kinase activity alters RyR2 phosphorylation and promotes poAF. In addition, he will develop improved atrial-specific gene therapy vectors for the delivery of SPEG kinase domains to atrial tissue. These preclinical studies may lead to the development of a target-based therapy for postoperative atrial fibrillation.

Public Health Relevance

The goal of this project is to determine the molecular mechanisms that lead to the development of atrial fibrillation following heart surgery. Juwan will focus on the role of a kinase called SPEG that modulates calcium cycling within atrial cells. Moreover, he will develop improved gene therapy vectors for the treatment of atrial fibrillation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL089598-11S1
Application #
10176268
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Balijepalli, Ravi C
Project Start
2007-08-01
Project End
2023-06-30
Budget Start
2020-09-23
Budget End
2021-06-30
Support Year
11
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Klipp, Robert C; Li, Na; Wang, Qiongling et al. (2018) EL20, a potent antiarrhythmic compound, selectively inhibits calmodulin-deficient ryanodine receptor type 2. Heart Rhythm 15:578-586
Pan, Xiaolu; Philippen, Leonne; Lahiri, Satadru K et al. (2018) In Vivo Ryr2 Editing Corrects Catecholaminergic Polymorphic Ventricular Tachycardia. Circ Res 123:953-963
Lezcano, N; Mariángelo, J I E; Vittone, L et al. (2018) Early effects of Epac depend on the fine-tuning of the sarcoplasmic reticulum Ca2+ handling in cardiomyocytes. J Mol Cell Cardiol 114:1-9
Yao, Chunxia; Veleva, Tina; Scott Jr, Larry et al. (2018) Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation. Circulation 138:2227-2242
Ni, Li; Scott Jr, Larry; Campbell, Hannah M et al. (2018) Atrial-Specific Gene Delivery Using an Adeno-Associated Viral Vector. Circ Res :
Auguste, Gaelle; Gurha, Priyatansh; Lombardi, Raffaella et al. (2018) Suppression of Activated FOXO Transcription Factors in the Heart Prolongs Survival in a Mouse Model of Laminopathies. Circ Res 122:678-692
Dobrev, Dobromir; Wehrens, Xander H T (2018) Mouse Models of Cardiac Arrhythmias. Circ Res 123:332-334
Wang, Qiongling; Quick, Ann P; Cao, Shuyi et al. (2018) Oxidized CaMKII (Ca2+/Calmodulin-Dependent Protein Kinase II) Is Essential for Ventricular Arrhythmia in a Mouse Model of Duchenne Muscular Dystrophy. Circ Arrhythm Electrophysiol 11:e005682
Wehrens, Xander H T (2018) Unraveling the Mechanisms by Which Calpain Inhibition Prevents Heart Failure Development. JACC Basic Transl Sci 3:518-520
Chiang, David Y; Alsina, Katherina M; Corradini, Eleonora et al. (2018) Rearrangement of the Protein Phosphatase 1 Interactome During Heart Failure Progression. Circulation 138:1569-1581

Showing the most recent 10 out of 130 publications