DNA Repair Mechanisms and Circadian Clock Disruption in the Cornea

角膜中的 DNA 修复机制和昼夜节律紊乱

• 批准号: 10332242
• 负责人: Shobhan Gaddameedhi
• 金额: $ 6.04万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-17 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10332242
• 关键词: Acute; Address; Affect; American; Biological Process; Blindness; Blood Vessels; Chronic; Cicatrix; Circadian Dysregulation; Circadian Rhythms; Cornea; DNA Damage; DNA Repair; Dependence; Disease; Ensure; Environment; Environmental Exposure; Exposure to; Eye; Eye Infections; Eyelid structure; Genes; Genetic; Genome Stability; Genomic Instability; Genotoxic Stress; Health; Human; Immune; Inbred HRS Mice; Infection; Inflammation; Inflammatory; Injury; Intervention; Jet Lag Syndrome; Keratoplasty; Knowledge; Lead; Left; Light; Maintenance; Malignant Neoplasms; Mediating; Mission; Molecular; Mus; National Institute of Environmental Health Sciences; Neoplasms; Nucleotide Excision Repair; Organ; Outcome; Outcome Study; Pathway interactions; Prevention; Process; Regulation; Research; Retina; Signal Transduction; Site; Skin; Skin Cancer; Structure; Sun Exposure; Sunburn; The Sun; Ultraviolet B Radiation; Wild Type Mouse; Work; base; circadian; circadian pacemaker; corneal epithelium; corneal repair; epithelial repair; improved; insight; lens; mouse model; parent grant; preventive intervention; response; shift work; tissue regeneration; tumor

Project Summary Approximately 42,000 Americans each year are in the need of a corneal transplant, with worldwide shortage of corneas for transplantation. The cornea is the transparent outermost protective layer of the eye. It forms the first barrier of the eye, and as such it is exposed to the environment. The cornea protects the internal structures of the eye and it focuses the light entering the eye on the lens before the light reaches the retina. The eyes and skin are the organs exposed to the sun and are therefore susceptible to DNA damage by solar UVB radiation, with eyelid tumors making up 5-10% of all skin cancers. Unlike the skin, a healthy cornea is devoid of blood vessels and it is a site of immune privilege. Injuries or infections of the eye can result in corneal inflammation that may lead to blindness if left untreated. Acute sun exposure can cause corneal photokeratitis while chronic exposure to the sun causes corneal sunburn, which can lead to vision loss due to inflammation and scarring, neoplasia or infection. Circadian disruption in mice is known to result in chronic corneal inflammation. Recent findings have shown that change in circadian rhythm has implications in corneal epithelial repair and maintenance. Understanding the consequences of environmental exposures such as solar UVB radiation and environmental disruption of the circadian clock such as jetlag conditions on corneal repair process would shed light on the underlying molecular mechanisms that influence corneal DNA repair and inflammation in humans. In humans and mice, nucleotide excision repair (NER) removes genetic damage caused by UVB. Therefore, protection from UVB exposure and ensuring efficient NER capacity are critical for maintenance of genomic stability, tissue renewal and for the prevention of neoplasia of the cornea. Our central hypothesis is that DNA repair in the cornea is undermined by the disruption of circadian rhythm, thus resulting in dysregulation of the inflammatory processes. Our study uses wildtype SKH1 hairless mice and circadian-disrupted Per1/2 genes defective SKH1 genetic mouse model and chronic jetlag simulated wildtype mice. In Aim 1a, we will determine the impact of UVB exposure on DNA repair and inflammation on wildtype SKH1 hairless mouse corneas. In Aim1b, we will characterize how circadian rhythm disruption would regulate DNA repair mechanisms and inflammatory pathways in mouse corneas using SKH1 hairless mice as proposed in the parent grant. The outcomes from these studies would provide mechanistic insight into the DNA repair and inflammatory processes occurring in the cornea and their dependency on circadian rhythm disruptions and will eventually lead to improved ocular therapies.

项目摘要 每年约有42,000名美国人需要角膜移植，全球 无法移植的角膜短缺。角膜是眼睛的最透明的保护层。它 形成眼睛的第一个障碍，因此暴露于环境。角膜保护内部 眼睛的结构并将光聚焦在光线到达视网膜之前的镜头上。这 眼睛和皮肤是暴露于太阳的器官，因此容易受到太阳能UVB的DNA损害 辐射，眼睑肿瘤占所有皮肤癌的5-10％。与皮肤不同，健康的角膜没有 血管，它是免疫特权的部位。眼睛受伤或感染可能导致角膜 如果未经治疗，可能会导致失明的炎症。急性阳光暴露会导致角膜光球炎 而长期暴露于阳光会导致角膜晒伤，这可能导致由于炎症而导致视力丧失 和疤痕，肿瘤或感染。已知小鼠的昼夜节律破坏会导致慢性角膜 炎。最近的发现表明，昼夜节律的变化对角膜上皮有影响 维修和维护。了解诸如太阳能UVB之类的环境暴露的后果 昼夜节律的辐射和环境破坏，例如角膜修复过程中的喷气lag条件 会阐明影响角膜DNA修复和炎症的基本分子机制 在人类中。在人类和小鼠中，核苷酸切除修复（NER）消除了UVB引起的遗传损害。 因此，防止UVB暴露并确保有效的NER容量对于维持至关重要 基因组稳定性，组织更新和预防角膜的肿瘤。我们的中心假设是 角膜中的DNA修复受到昼夜节律的破坏而破坏的，从而导致失调 炎症过程。我们的研究使用WildType SKH1无毛小鼠和昼夜节律中断的PER1/2基因 有缺陷的SKH1遗传小鼠模型和慢性喷气lag模拟野生型小鼠。在AIM 1A中，我们将确定 UVB暴露对DNA修复和炎症对野生型SKH1无毛小鼠角膜的影响。在 AIM1B，我们将表征昼夜节律中断如何调节DNA修复机制和 父母赠款中提出的使用SKH1无毛小鼠在小鼠角膜中的炎症途径。这 这些研究的结果将提供对DNA修复和炎症过程的机械洞察力 发生在角膜及其对昼夜节律中断的依赖，最终将导致 改进的眼部疗法。