Ion Channels and Pumps: The Machinery of Electric Signaling at Corneal Wounds ABSTRACT Corneal epithelial cells migrate and proliferate;importantly they do so directionally, to heal wounds. Growth factors and cytokines play pivotal roles in wound healing and may be potential targets for corneal wound therapies. We have discovered a very different factor, namely naturally-occurring electric fields (EFs) at corneal wounds that also activate intracellular pathways. More significantly, because EFs are intrinsically directional, they activate signaling pathways directionally, giving cells a directional cue and guiding cells to migrate and divide in the direction of the wound to facilitate healing. Our studies have shown that EFs override other well-accepted directional cues such as contact inhibition release, wound void, population pressure and chemotaxis to guide cell migration in a defined direction. How the endogenous EFs are generated and regulated is not known. In streptozotocin (STZ)- induced type 1 diabetes mellitus rats and Pax6+/- mutant mice that have defective corneal wound healing, we observed significantly reduced endogenous wound EFs. Can we enhance the endogenous wound EFs to enhance wound healing, especially in refractory and chronic wounds? Our long-term goal is to elucidate the mechanisms through which electric signals can be exploited to accelerate wound healing. We recently observed that wound EFs increase gradually following injury, and substitution of Cl- or Na+ in the bathing solution significantly alters the endogenous EFs. We thus hypothesize that injury to the cornea induces actively-regulated wound electric fields, which are formed by fluxes of specific ions (e.g. Cl-) that are controlled by Cl- channels and transport molecules; manipulating Cl- flux may enhance endogenous electric fields and wound healing. We will test this hypothesis with the following Specific Aims:
Aim 1. To confirm that wound electric fields are an active response to injury.
Aim 2. To determine the ionic mechanisms of endogenous EFs at corneal wounds.
Aim 3. To elucidate the molecular mechanisms of wound electric fields. The results from this proposal will define the active electric signaling in corneal wound healing, provide ionic and molecular mechanisms of electric signaling in wound healing, and may lead to novel therapies to improve wound healing exploiting electric signaling.

Public Health Relevance

Persistent corneal epithelial defects pose an important medical problem. We recently discovered a novel signaling mechanism at corneal wounds, namely naturally-occurring electric fields that have profound guidance effects on epithelial cells to heal wounds. This project seeks to determine the ionic and molecular mechanisms controlling ionic fluxes at corneal wounds. The scientific knowledge to be acquired through this project, i.e. how cells regulate this fundamental signal, will open a new avenue to treat delayed and non-healing corneal wounds, and wounds in general.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019101-04
Application #
8389547
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
2009-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2013
Total Cost
$351,120
Indirect Cost
$123,120
Name
University of California Davis
Department
Dermatology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Zhao, Siwei; Zhu, Kan; Zhang, Yan et al. (2014) ElectroTaxis-on-a-Chip (ETC): an integrated quantitative high-throughput screening platform for electrical field-directed cell migration. Lab Chip 14:4398-405
Ozkucur, Nurdan; Song, Bing; Bola, Sharanya et al. (2014) NHE3 phosphorylation via PKC? marks the polarity and orientation of directionally migrating cells. Cell Mol Life Sci 71:4653-63
Tran, Vu; Zhang, Xiaodong; Cao, Lin et al. (2013) Synchronization modulation increases transepithelial potentials in MDCK monolayers through Na/K pumps. PLoS One 8:e61509
Zhao, Sanjun; Gao, Runchi; Devreotes, Peter N et al. (2013) 3D arrays for high throughput assay of cell migration and electrotaxis. Cell Biol Int 37:995-1002
Rudell, Jolene Chang; Gao, Jing; Sun, Yuxin et al. (2013) Acanthamoeba migration in an electric field. Invest Ophthalmol Vis Sci 54:4225-33
Sun, Yaohui; Do, Hao; Gao, Jing et al. (2013) Keratocyte fragments and cells utilize competing pathways to move in opposite directions in an electric field. Curr Biol 23:569-74
Cao, Lin; Wei, Dongguang; Reid, Brian et al. (2013) Endogenous electric currents might guide rostral migration of neuroblasts. EMBO Rep 14:184-90
Zhao, Min; Chalmers, Laura; Cao, Lin et al. (2012) Electrical signaling in control of ocular cell behaviors. Prog Retin Eye Res 31:65-88
Feng, Jun-Feng; Liu, Jing; Zhang, Xiu-Zhen et al. (2012) Guided migration of neural stem cells derived from human embryonic stem cells by an electric field. Stem Cells 30:349-55
Zhao, Zhiqiang; Qin, Lu; Reid, Brian et al. (2012) Directing migration of endothelial progenitor cells with applied DC electric fields. Stem Cell Res 8:38-48

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