This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Gap junction communication is critical for fundamental biological processes in the heart including growth and development, impulse propagation and responses to physiological and pathological stimuli. Of the 2 cardiac connexins expressed in working ventricular myocytes, far less is known about the distribution and function of Cx45 than the principal ventricular gap junction channel protein, Cx43. The long-term goal of our laboratory is to define the role of Cx45 in normal and diseased hearts.
The Specific Aims of this application are focused on 4 aspects of Cx45 function in the normal heart: 1) interaction with Cx43 at intercellular junctions;2) biophysical characterization of Cx45/Cx43 hybrid gap junction channels;3) mechanisms regulating changes in Cx45 expression in response to physiological stimuli;and 4) alterations in intercellular coupling resulting from increased expression of Cx45 relative to Cx43.
In Aim 1, double-label immunoelectron microscopy will be used to determine the subcellular colocalization of Cx45 and Cx43 in cardiac gap junctions.
In Aim 2, single channel recordings via dual whole-cell voltage-clamp procedures will be used to elucidate unique properties of Cx45/Cx43 hybrid gap junction channels in native ventricular myocytes from wild-type, transgenic Cx45-overexpressing and Gx43-null mice.
In Aim 3, cardiac myocytes will be subjected to defined pulsatile stretch to induce upregulation of Cx45 expression;mechanisms responsible for this acute response to mechanical stimulation including changes in Cx45 trafficking and activation of integrin signaling pathways will be delineated.
In Aim 4, Lucifer yellow dye transfer studies in myocytes expressing different levels of Cx45 and Cx43 will reveal how increased expression of Cx45 relative to Cx43 alters intercellular coupling. These studies will provide new insights into homeostatic mechanisms controlling distribution of Cx45 and Cx43 in the normal heart, and how connexin remodeling in disease states such as myocardial ischemia, adaptive hypertrophy and end-stage heart failure disrupts normal intercellular communication.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BCMB-K (40))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
Yue, Xuyi; Dhavale, Dhruva D; Li, Junfeng et al. (2018) Design, synthesis, and in vitro evaluation of quinolinyl analogues for ?-synuclein aggregation. Bioorg Med Chem Lett 28:1011-1019
Ohlemacher, Shannon I; Giblin, Daryl E; d'Avignon, D André et al. (2017) Enterobacteria secrete an inhibitor of Pseudomonas virulence during clinical bacteriuria. J Clin Invest 127:4018-4030
Lin, Xiaobo; Racette, Susan B; Ma, Lina et al. (2017) Endogenous Cholesterol Excretion Is Negatively Associated With Carotid Intima-Media Thickness in Humans. Arterioscler Thromb Vasc Biol 37:2364-2369
Ovod, Vitaliy; Ramsey, Kara N; Mawuenyega, Kwasi G et al. (2017) Amyloid ? concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement 13:841-849
Cade, W Todd; Levy, Philip T; Tinius, Rachel A et al. (2017) Markers of maternal and infant metabolism are associated with ventricular dysfunction in infants of obese women with type 2 diabetes. Pediatr Res 82:768-775
Lucey, Brendan P; Mawuenyega, Kwasi G; Patterson, Bruce W et al. (2017) Associations Between ?-Amyloid Kinetics and the ?-Amyloid Diurnal Pattern in the Central Nervous System. JAMA Neurol 74:207-215
Wei, Xiaochao; Song, Haowei; Yin, Li et al. (2016) Fatty acid synthesis configures the plasma membrane for inflammation in diabetes. Nature 539:294-298
Shields-Cutler, Robin R; Crowley, Jan R; Miller, Connelly D et al. (2016) Human Metabolome-derived Cofactors Are Required for the Antibacterial Activity of Siderocalin in Urine. J Biol Chem 291:25901-25910
Mertins, Philipp; Mani, D R; Ruggles, Kelly V et al. (2016) Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 534:55-62
Murata, Takahiro; Dietrich, Hans H; Horiuchi, Tetsuyoshi et al. (2016) Mechanisms of magnesium-induced vasodilation in cerebral penetrating arterioles. Neurosci Res 107:57-62

Showing the most recent 10 out of 696 publications