Ion Channels and Pumps: The Machinery of Electric Signaling at Corneal Wounds

离子通道和泵：角膜伤口的电信号机制 摘要 角膜上皮细胞迁移、增殖；重要的是他们这样做是有方向的，为了治愈 伤口。生长因子和细胞因子在伤口愈合中发挥关键作用，可能是潜在的目标 用于角膜伤口治疗。我们发现了一个非常不同的因素，即自然发生的因素 角膜伤口处的电场（EF）也会激活细胞内通路。更重要的是， 因为 EF 本质上是定向的，它们定向激活信号通路，为细胞提供 定向提示并引导细胞向伤口方向迁移和分裂，以促进愈合。 我们的研究表明，EF 优先于其他广为接受的方向线索，例如接触 抑制释放、伤口空隙、群体压力和趋化性，以引导细胞在规定的范围内迁移 方向。内源性 EF 是如何产生和调节的尚不清楚。在链脲佐菌素 (STZ) 中- 诱发 1 型糖尿病的大鼠和具有缺陷角膜伤口的 Pax6/- 突变小鼠 在愈合过程中，我们观察到内源性伤口 EF 显着降低。能否增强内生性 伤口 EF 可以促进伤口愈合，特别是难治性和慢性伤口？我们的长期目标 目的是阐明利用电信号加速伤口愈合的机制 治愈。我们最近观察到，伤口 EF 在受伤后逐渐增加，并且替代 沐浴液中的 Cl- 或 Na 会显着改变内源 EF。因此我们假设 角膜损伤会诱发主动调节的伤口电场，该电场由通量形成 由 Cl- 通道和转运分子控制的特定离子（例如 Cl-）； 控制 Cl-通量可以增强内源电场和伤口愈合。我们将测试 该假设具有以下具体目标： 目标 1. 确认伤口电场是 对伤害的积极反应。目标 2. 确定角膜内源性 EF 的离子机制 伤口。目标 3. 阐明伤口电场的分子机制。由此得出的结果 该提案将定义角膜伤口愈合中的主动电信号传导，提供离子和分子信号 伤口愈合中的电信号传导机制，并可能导致改善伤口的新疗法 利用电信号进行治疗。

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.