Our goal is to electrically heal wounds. Experiments from our own lab and others have demonstrated that electric fields occur naturally at corneal wounds and provide a powerful signal to guide migration of corneal epithelial cells. We demonstrated that the electrical signals could override other directional cues, such as injury stimulation, free edge and mechanical forces, in guiding migration of corneal epithelial sheets and large groups of cells. It is however not known how cornea wounds generate the electric signal. We propose to discover molecular generators at corneal wounds. Uncovering these generator molecules will give us molecular targets which we can stimulate to produce stronger electrical signals, and thus facilitate healing. In this proposal, we will 1) characterize calcium-activated chloride channels (CaCCs) in corneal epithelial cells using electrophysiology and genetic models; 2) determine responses of CaCCs to injury and their roles in generating wound electric currents; and, 3) correct the defective wound electric signals (and wound healing) in diabetic rats and ANO1 knockout mice. We expect that the novel mechanisms discovered will provide fundamental insights as well as practical strategies for healing of chronic corneal wounds.

Public Health Relevance

Electric fields occur naturally at corneal wounds, with the field polarity orientated towards the wound center. These electric fields send a powerful signal to instigate directional migration of corneal epithelial cells to heal wounds. We will investigate the molecular mechanisms of the generation and regulation of the wound electric signal, and develop strategies to regulate the electrical currents to achieve better healing of corneal wounds. This project will identify new important targets for improving defective wound healing, for example in diabetic patients.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019101-06
Application #
9039611
Study Section
Biology of the Visual System Study Section (BVS)
Program Officer
Mckie, George Ann
Project Start
2008-07-01
Project End
2019-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
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
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
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
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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