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，以愈合 伤口生长因子和细胞因子在创伤愈合过程中起着关键作用，可能是潜在的靶点 用于角膜创伤治疗。我们发现了一个非常不同的因素，即自然发生的 在角膜伤口处的电场（EF）也激活细胞内通路。更重要的是， 由于EF具有内在的方向性，它们定向激活信号通路，使细胞 定向提示并引导细胞在伤口方向上迁移和分裂以促进愈合。 我们的研究已经表明，EF覆盖其他广为接受的方向线索，如接触 抑制释放，伤口空隙，群体压力和趋化性，以引导细胞迁移，在一个定义的 方向内源性EF如何产生和调节尚不清楚。在链脲佐菌素（STZ）中- 诱导的1型糖尿病大鼠和具有缺陷性角膜伤口的Pax 6 +/-突变小鼠 愈合后，我们观察到内源性伤口EF显著降低。我们能不能增强 伤口EF，以促进伤口愈合，特别是在难治性和慢性伤口？我们的长期目标 是阐明电信号可以用来加速伤口愈合的机制 治愈我们最近观察到，伤口EF在损伤后逐渐增加， 浸浴液中的Cl-或Na+显著改变内源性EFs。因此，我们假设， 角膜损伤诱导主动调节的伤口电场， 由Cl-通道和转运分子控制的特定离子（例如Cl-）; 操纵Cl-通量可增强内源性电场和伤口愈合。我们将测试 这个假设有以下具体目标：目标1。为了证实伤口电场是 积极应对伤害。目标2.确定角膜内源性EFs的离子机制， 伤口目标3：阐明创伤电场的分子机制。结果是 该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 的电信号机制，并可能导致新的疗法，以改善伤口愈合 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.