UVR-INDUCED DNA DAMAGE AND ANGIOGENIC GROWTH FACTORS

紫外线引起的 DNA 损伤和血管生成因子

• 批准号: 3265705
• 负责人: RONALD D LEY
• 金额: $ 11.78万
• 依托单位: LOVELACE RESPIRATORY RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 1995-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3265705
• 关键词: DNA damage; DNA repair; angiogenesis; angiogenesis factor; cornea disorder; corneal epithelium; endodeoxyribonuclease; gel electrophoresis; genetic library; histopathology; immunocytochemistry; in situ hybridization; lens; northern blottings; nucleic acid probes; opossums; protein biosynthesis; pyrimidine dimers; radiation carcinogen; radiation carcinogenesis; solar radiation; ultraviolet radiation

Skin and eyes are the only organs of the body that are exposed directly to solar ultraviolet radiation (UVR). It has been shown that xeroderma pigmentosum individuals are deficient in DNA repair and have an increased susceptibility to UVR-induced opacification and neovascularization of the cornea and cancer of the anterior eye. The prospect of stratospheric ozone depletion and the accompanying increase in human exposure to UVR makes it imperative that we understand the acute and chronic responses of the mammalian eye to UVR exposure. The marsupial Monodelphis domestica is an experimental animal model uniquely suited for studies on the role of a specific UVR-induced DNA lesion, the pyrimidine dimer, in causing pathological changes in eyes exposed to UVR. As in the epidermis, cells in the corneal epithelium of M. domestica have a high capacity for the photoreactivation (PR) repair of UVR-induced pyrimidine dimers. The light-dependent PR repair pathway has the unique property of repairing only pyrimidine dimers; therefore, if PR decreases the ability of UVR to induce a photobiological response, it is generally accepted that pyrimidine dimers are in some way involved in initiating that response. Chronic UVR exposure of M. domestica induces tumors of the cornea. UVR induces proliferation of corneal stromocytes and endothelial cells which precedes tumor development. It seems reasonable to assume that UVR in some way induces the synthesis or secretion of mitogenic and angiogenic growth factors that act in an autocrine or paracrine manner to stimulate proliferation of corneal stromocytes and endothelial cells. The proposed research will lest the hypothesis that unrepaired pyrimidine dimers in DNA alters the synthesis and/or release of mitogenic and angiogenic growth factors in the UVR-exposed cornea. These early molecular events may result in enhanced susceptibility to UVR-induced cancer. The specific aims are: 1) RNA blotting and standard histological techniques will be used to determine the time course of angiogenic growth factor expression and pathological changes that occur in the chronically-irradiated cornea. PR will be used to define a role for DNA damage in these processes; 2) in situ hybridization and immunohistochemical staining will be used to identify the site of synthesis and/or release of angiogenic growth factors in the chronically irradiated cornea; and, 3) as an extension of studies on DNA repair in corneal epithelium, damage-specific nucleases in conjunction with alkaline gel electrophoresis will be used to measure the excision and photoreactivation repair of UVR-induced pyrimidine dimers in lens epithelial DNA.

皮肤和眼睛是人体唯一直接接触到的器官