Intercellular communication plays diverse roles in the embryological and postnatal development of the heart. Correspondingly, insight into developmental mechanisms governing the organization of cell-cell coupling may significantly inform the origins of electrophysiological instabilities in the diseased heart. The disorganized patterns of cell coupling common to various pathologies of the myocardium, re-capitulate patterns of gap junction (gj) distribution found in differentiating myocardium. As detailed herein, we have made significant progress in understanding patterning of gjs in the developing heart - also laying a foundation for renewal of this project. In particular, we have developed strong evidence for a novel potential function of a connexin interacting protein, ZO-1, in gj remodeling. Our specific hypothesis is that a ZO-1 basedmechanism has a role in a gj endocytosis process that may impact developmental remodeling of electrical coupling patterns between myocytes. In addition, we have derived evidence for a role for coronary arteriogenesis in determining gj distribution and connexin expression in studies of a transgenic model of sudden cardiac death (the HF1b knockout mouse). To build on these observations we aim to; 1) use membrane translocating peptides and adenoviral vectors to target ZO-1-Cx43 interactions, investigating the role of ZO-l in Cx43 gj remodeling in Langendorff perfused heart and cell culture preparations ; 2) use fluorescent ZO-1 and Cx43 fusion proteins, and stably transfected cell lines, to directly observed ZO-I-Cx43 interactions and Cx43 gj function in vivo ; 3) use adenoviral vectors and inhibitory peptides targeting ZO-l-Cx43 interactions to investigate the role of ZO-1 in Cx43 gj patterning in cardiac development and disease; and ; 4) characterize whether loss of ZO-I function and/or abnormalities in coronary arteriogenesis have a role in defective gj patterning in the working myocardium and ventricular conduction tissues of the HF lb knockout mouse heart.
| Hoagland, Daniel T; Santos, Webster; Poelzing, Steven et al. (2018) The role of the gap junction perinexus in cardiac conduction: Potential as a novel anti-arrhythmic drug target. Prog Biophys Mol Biol : |
| Lindsey, Merry L; Bolli, Roberto; Canty Jr, John M et al. (2018) Guidelines for experimental models of myocardial ischemia and infarction. Am J Physiol Heart Circ Physiol 314:H812-H838 |
| Grek, Christina L; Sheng, Zhi; Naus, Christian C et al. (2018) Novel approach to temozolomide resistance in malignant glioma: connexin43-directed therapeutics. Curr Opin Pharmacol 41:79-88 |
| Montgomery, Jade; Ghatnekar, Gautam S; Grek, Christina L et al. (2018) Connexin 43-Based Therapeutics for Dermal Wound Healing. Int J Mol Sci 19: |
| Raisch, Tristan B; Yanoff, Matthew S; Larsen, Timothy R et al. (2018) Intercalated Disk Extracellular Nanodomain Expansion in Patients With Atrial Fibrillation. Front Physiol 9:398 |
| Veeraraghavan, Rengasayee; Hoeker, Gregory S; Alvarez-Laviada, Anita et al. (2018) The adhesion function of the sodium channel beta subunit (?1) contributes to cardiac action potential propagation. Elife 7: |
| Jiang, Jingbo; He, Huamei; Gourdie, Robert G et al. (2017) [Ischemia/reperfusion injury study in isolated mouse hearts using a pressure-volume curve]. Zhonghua Yi Xue Za Zhi 97:2691-2696 |
| George, Sharon A; Calhoun, Patrick J; Gourdie, Robert G et al. (2017) TNF? Modulates Cardiac Conduction by Altering Electrical Coupling between Myocytes. Front Physiol 8:334 |
| Rhett, J Matthew; Calder, Bennett W; Fann, Stephen A et al. (2017) Mechanism of action of the anti-inflammatory connexin43 mimetic peptide JM2. Am J Physiol Cell Physiol 313:C314-C326 |
| Greer, Kisha; Chen, Jiang; Brickler, Thomas et al. (2017) Modulation of gap junction-associated Cx43 in neural stem/progenitor cells following traumatic brain injury. Brain Res Bull 134:38-46 |
Showing the most recent 10 out of 64 publications
