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 角膜上皮细胞迁移和增殖；重要的是，它们定向地这样做，以治愈 伤口。生长因子和细胞因子在伤口愈合中起着关键作用，可能成为潜在的靶点。 用于角膜创伤治疗。我们发现了一个非常不同的因素，那就是自然发生的 角膜伤口处的电场(EFS)也会激活细胞内通路。更重要的是， 因为EFS本质上是方向性的，它们定向地激活信号通路，给细胞 定向提示和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，EFS优先于其他被广泛接受的定向线索，如联系 抑制释放，伤口空洞，群体压力和趋化性，以引导细胞在确定的 方向。内源性EFS是如何产生和调控的，目前尚不清楚。链脲佐菌素(STZ)- 诱导的1型糖尿病大鼠和Pax6/-突变小鼠的角膜损伤 愈合后，我们观察到内源性创面EFS明显减少。我们能增强内生性吗 创面EFS促进创面愈合，尤其是难治性和慢性创面？我们的长期目标 是阐明电信号可以被用来加速伤口的机制 治愈。我们最近观察到，创伤后创面EFS逐渐增加，并取代 浴液中的Cl-或Na离子显著改变内源EFS。因此，我们假设 角膜损伤诱导主动调节的伤口电场，这种电场是由通量形成的。 由氯离子通道和运输分子控制的特定离子(例如，氯离子)； 控制氯离子通量可增强内源性电场，促进创面愈合。我们将测试 这一假说有以下具体目的：目的1.证实缠绕电场是一种 对受伤的积极反应。目的2.确定角膜内源性EFS的离子机制 伤口。目的3.阐明创伤电场的分子机制。由此产生的结果是 提案将定义角膜伤口愈合中的主动电信号，提供离子和分子 伤口愈合中的电信号机制，并可能导致新的治疗方法来改善伤口 治愈利用电信号。

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.