The long-term goals of our laboratory are: a) to understand the molecular mechanisms that regulate cardiac gap junctions and b) to apply that knowledge to the development of pharmacologic agents able to modify gap junction regulation and function. It is generally accepted that the carboxyl terminal is the major regulatory domain of Connexin43 (Cx43) channels. Our previous work has led to the hypothesis that regulation of Cx43 results from the binding of the carboxyl terminal (Cx43CT) domain -acting as a gating particle- to the cytoplasmic loop (Cx43CL) domain, acting as a receptor for the gating particle. Cx43CT dimerization and other intermolecular interactions involving the same domain may also participate in the process. As a key player in the regulation of gap junctions, the Cx43CT domain is a target for chemical manipulation intended to modify function. Recently, we reported the identification of a peptidic molecule, dubbed """"""""RXPE,"""""""" that bound Cx43CT with micromolar affinity and partly prevented octanol-induced and acidification-induced uncoupling in pairs of Cx43-expressing N2a cells. Preliminary data presented in this application further show that RXPE binds cardiac Cx43, facilitates the synchronization of electrical activity in monolayers of neonatal cardiac myocytes, and prevents heptanol-induced conduction block in the same preparation. It is the overall objective of this project to use RXP-E as a platform in the development of a gap junction- based pharmacophore of known cellular/molecular action, and to assess its possible efficacy in the maintenance of electrical synchrony in cardiac preparations.
Specific aims are: 1: To characterize the effect of RXP-E on the molecular events mediating Cx43 regulation. 2: To analyze the actions of RXP-E on the chemical regulation of cardiac gap junctions, and on the electrophysiology of single cardiac myocytes, and 3: To assess the effect of RXP-E on cardiac action potential propagation, susceptibility to conduction block and arrhythmogenesis. Overall, these studies may lead to a better understanding of the role of gap junctions in the development of ischemia-induced arrhythmias and their possible intervention by chemical means.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM057691-14
Application #
8244843
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Rivera-Rentas, Alberto L
Project Start
1999-05-01
Project End
2013-05-31
Budget Start
2010-10-01
Budget End
2013-05-31
Support Year
14
Fiscal Year
2010
Total Cost
$376,820
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Trembley, Michael A; Quijada, Pearl; Agullo-Pascual, Esperanza et al. (2018) Mechanosensitive Gene Regulation by Myocardin-Related Transcription Factors Is Required for Cardiomyocyte Integrity in Load-Induced Ventricular Hypertrophy. Circulation 138:1864-1878
Rona, Gergely; Roberti, Domenico; Yin, Yandong et al. (2018) PARP1-dependent recruitment of the FBXL10-RNF68-RNF2 ubiquitin ligase to sites of DNA damage controls H2A.Z loading. Elife 7:
Rivaud, Mathilde R; Agullo-Pascual, Esperanza; Lin, Xianming et al. (2017) Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes. J Am Heart Assoc 6:
Te Riele, Anneline S J M; Agullo-Pascual, Esperanza; James, Cynthia A et al. (2017) Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis. Cardiovasc Res 113:102-111
Cerrone, Marina; Montnach, Jerome; Lin, Xianming et al. (2017) Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm. Nat Commun 8:106
Yin, Yandong; Rothenberg, Eli (2016) Probing the Spatial Organization of Molecular Complexes Using Triple-Pair-Correlation. Sci Rep 6:30819
Leo-Macias, Alejandra; Agullo-Pascual, Esperanza; Delmar, Mario (2016) The cardiac connexome: Non-canonical functions of connexin43 and their role in cardiac arrhythmias. Semin Cell Dev Biol 50:13-21
Dubash, Adi D; Kam, Chen Y; Aguado, Brian A et al. (2016) Plakophilin-2 loss promotes TGF-?1/p38 MAPK-dependent fibrotic gene expression in cardiomyocytes. J Cell Biol 212:425-38
Leo-Macias, Alejandra; Agullo-Pascual, Esperanza; Sanchez-Alonso, Jose L et al. (2016) Nanoscale visualization of functional adhesion/excitability nodes at the intercalated disc. Nat Commun 7:10342
Shekhar, Akshay; Lin, Xianming; Liu, Fang-Yu et al. (2016) Transcription factor ETV1 is essential for rapid conduction in the heart. J Clin Invest 126:4444-4459

Showing the most recent 10 out of 48 publications