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

角膜伤口处的分子发生器产生并调节伤口电信号

基本信息

批准号：
10374031
负责人：
Min Zhao
金额：
$ 38.07万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10374031
关键词：
Active Ion Transport Address Affect Awareness Binding Cells Charge Chronic Cornea Corneal Injury Cues Data Defect Development Diabetes Mellitus Disease Electric Stimulation Electrical Resistance Electrophysiology (science)Environment Epithelial Epithelial Cells Exhibits Generations Glean Glucose Goals Hour Human Impaired healing Impairment In Vitro Injury Insurance Ions Knowledge Metabolic Methods Modeling Molecular Molecular Genetics Muscle Natural regeneration Nature Nerve Organ Culture Techniques Organism Oxygen Pharmacologic Substance Physiologic pulse Physiological Regulation Research Rest Role Signal Transduction Site Tissues United States Centers for Medicare and Medicaid Services Wound models bioelectricity chronic wound clinical application corneal epithelial wound healing corneal epithelium diabetic diabetic ulcer diabetic wound healing electric field electrical potential experimental study healing high throughput screening improved in vivo insight mathematical model mechanical force migration millisecond non-diabetic non-healing wounds novel novel therapeutic intervention response segregation small molecule spatiotemporal tissue culture uptake vector wound wound healing

项目摘要

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.

摘要（说明）活的和完整的角膜保持跨上皮的电势差，跨上皮的电势差是通过角膜上皮细胞的跨膜电位。电位差（TEP）。角膜伤口中受损的上皮屏障使角膜上皮细胞破裂，在伤口部位的跨上皮电位，导致自然发生的内源性电场，从邻近的完整组织指向伤口中心。这些自然产生的伤口电场（wEF）提供刺激和引导细胞迁移到伤口中以启动伤口愈合的强大信号。治愈我们证明了这些电信号可以覆盖其他方向性线索，如损伤刺激、自由边缘和机械力，在引导角膜上皮层迁移中的作用，大量的细胞。我们的长期目标是阐明产生和调节伤口电场，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）来治愈慢性伤口，无法愈合的伤口我们以前的研究已经确定了关键的离子机制和“分子机制”，发电机”，生产和调节wEFs。重要的是，我们在三个糖尿病模型中证明， wEF是有缺陷的，这与受损的愈合非常相关。使用高通量筛选，我们还发现了指导人类角膜上皮细胞反应的新分子机制，（CEC）生理电场。在这个应用中，我们将剖析有缺陷的电信号以及糖尿病角膜上皮细胞的受损反应。因此，我们提出一项全面的研究（1）阐明糖尿病角膜中缺陷性电信号的离子机制伤口，并建立一个数学模型，模拟伤口电场;（2）确定有多高葡萄糖和氧摄取调节产电机制，以及这些机制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），以电力促进愈合通过纠正电信号产生中的缺陷来治疗糖尿病伤口。