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
Tai, Guangping; Tai, Michael; Zhao, Min (2018) Electrically stimulated cell migration and its contribution to wound healing. Burns Trauma 6:20
Sun, Xiaoyan; Qi, Hongsheng; Zhang, Xiuzhen et al. (2018) Src activation decouples cell division orientation from cell geometry in mammalian cells. Biomaterials 170:82-94
Sun, Yao-Hui; Sun, Yuxin; Zhu, Kan et al. (2018) Electric fields accelerate cell polarization and bypass myosin action in motility initiation. J Cell Physiol 233:2378-2385
Feng, Jun-Feng; Liu, Jing; Zhang, Lei et al. (2017) Electrical Guidance of Human Stem Cells in the Rat Brain. Stem Cell Reports 9:177-189
Zhang, Yan; Xu, Guoqing; Lee, Rachel M et al. (2017) Collective cell migration has distinct directionality and speed dynamics. Cell Mol Life Sci 74:3841-3850
Nakajima, Ken-Ichi; Zhao, Min (2016) Concerted action of KCNJ15/Kir4.2 and intracellular polyamines in sensing physiological electric fields for galvanotaxis. Channels (Austin) 10:264-6
Zhu, Kan; Sun, Yaohui; Miu, Anh et al. (2016) cAMP and cGMP Play an Essential Role in Galvanotaxis of Cell Fragments. J Cell Physiol 231:1291-300
Shen, Yunyun; Pfluger, Trisha; Ferreira, Fernando et al. (2016) Diabetic cornea wounds produce significantly weaker electric signals that may contribute to impaired healing. Sci Rep 6:26525
Sun, Yao-Hui; Sun, Yuxin; Zhu, Kan et al. (2016) An Experimental Model for Simultaneous Study of Migration of Cell Fragments, Single Cells, and Cell Sheets. Methods Mol Biol 1407:251-72
Gao, Runchi; Zhao, Siwei; Jiang, Xupin et al. (2015) A large-scale screen reveals genes that mediate electrotaxis in Dictyostelium discoideum. Sci Signal 8:ra50

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