Molecular Generators at Corneal Wounds Produce and regulate the Wound Electrical Signals

摘要(描述) 活的和完整的角膜在上皮、跨上皮和跨上皮之间保持电势差 电位差(TEP)。角膜创伤中受损的上皮屏障使角膜塌陷 伤口处的跨上皮电位，导致自然产生的内源性电场 从邻近完整的组织指向伤口中心。这些自然产生的电伤 电场(WEf)提供强大的信号，刺激和引导细胞迁移到伤口内启动 治愈。我们证明了这些电信号可以覆盖其他定向信号，例如 损伤刺激，自由边缘和机械力，在引导角膜上皮片和 一大群细胞。我们的长期目标是阐明产生和 调节缠绕的电场，即发现“分子发电机”，并利用这一知识 开发新的治疗策略，以集体动员细胞(组织)来修复慢性伤口和 无法愈合的伤口。我们之前的研究已经确定了关键的离子机制和分子 产生和调节WEF的“发电机”。重要的是，我们在三个糖尿病模型中证明了 WEF是有缺陷的，这与受损的愈合有很好的相关性。使用高吞吐量的筛网， 我们还发现了指导人类角膜上皮细胞反应的新的分子机制 (CECs)到生理电场。在这个应用中，我们将剖析有缺陷的电信号 糖尿病角膜上皮细胞反应受损。因此，我们提出了一项全面的 糖尿病角膜电信号缺陷离子机制的研究(1) 并建立模拟伤口电场的数学模型；(2)确定有多高 葡萄糖和氧气摄取调节发电机制，以及这些机制是如何在 糖尿病角膜。通过完成这些目标，我们的目标是目标(3)，以电气促进治愈 通过纠正电信号产生的缺陷来治疗糖尿病伤口。

Abstract (Description) Live and intact cornea maintains an electric potential difference across the epithelium, the transepithelial potential difference (TEP). The compromised epithelial barrier in corneal wounds collapses the transepithelial potential at the wound site, resulting in naturally occurring endogenous electric fields that point towards the wound center from adjacent intact tissues. These naturally occurring wound electric fields (wEFs) provide powerful signals that stimulate and guide cells to migrate into the wound to initiate healing. We demonstrated that these 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. Our long term goal is to elucidate the molecular mechanisms that generate and regulate the wound electric fields, i.e. to discover the “molecular generators”, and to use this knowledge to develop new therapeutic strategies to collectively mobilize cells (tissues) to heal chronic wounds and non-healing wounds. Our previous research has identified key ionic mechanisms and “molecular generators” that produce and regulate wEFs. Importantly, we demonstrated in three diabetic models that wEFs are defective and this correlates very well with impaired healing. Using high throughput screens, we also identified novel molecular mechanisms directing the responses of human corneal epithelial cells (CECs) to physiological electric fields. In this application, we will dissect the defective electrical signaling and impaired responses of epithelial cells in diabetic cornea. We therefore propose a comprehensive study to (1) elucidate ionic mechanisms underlying defective electrical signaling in diabetic corneal wounds, and to build a mathematical model that simulates wound electric fields; (2) determine how high glucose and oxygen uptake regulate electrogenic machinery, and how these mechanisms are impaired in diabetic cornea. Through completion of these aims, our goal is Aim (3) to electrically facilitate healing of diabetic wounds by correcting defects in generation of electrical signals.