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.

项目总结