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Mechanisms elicited by type I interferons in cutaneous photocarcinogenesis

I 型干扰素引起皮肤光致癌的机制

基本信息

批准号：
9764280
负责人：
Nabiha Yusuf
金额：
$ 41.51万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-20 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9764280
关键词：
Address Binding Biological Response Modifiers Cell Proliferation Chronic Cutaneous DNA Damage DNA Repair DNA Repair Gene DNA biosynthesis Development Disease Dose Environmental Carcinogens Exposure to Generations Genetic Transcription High Prevalence Human IFNAR1 gene Immune response Immunosuppression Interferon Receptor Interferon Type I Interferon-beta Interferons Knockout Mice Lesion Malignant Neoplasms Mediating Messenger RNA Modeling Mouse Protein Mus Mutation Myelogenous Natural Immunity Pathway interactions Play Post-Transcriptional Regulation Premalignant Prevention Prevention strategy Process Production Protein Splicing Proteins Pyrimidine Dimers Radiation Induced DNA Damage Regulation Role Signal Pathway Signal Transduction Skin Skin Cancer Skin Neoplasms Solar Energy TLR4 gene Testing Transcriptional Regulation Tumor Suppressor Genes UV carcinogenesis UVB induced Ultraviolet B Radiation Ultraviolet Rays Up-Regulation Virus Diseases Wild Type Mouse base carcinogenicity cell type cytokine genetic signature knockout gene mRNA Decay mouse model pathogen prevent receptor repaired response skin lesion small molecule tumor ultraviolet

项目摘要

ABSTRACT Type I interferons (IFNs) are cytokines, that are important regulators of immune responses and are downregulated in human cancers, including skin cancer, Solar ultraviolet (UV) radiation is a proven environmental carcinogen, and exposure to solar radiation contributes to the high prevalence of skin cancer. The carcinogenic effects of UV light can be attributed to the formation of cyclobutane pyrimidine dimers (CPD) and errors in repair and replication of DNA. It is believed that type I IFNs reduce cellular proliferation and allow DNA repair in various diseases. This suggests that type I IFNs may play a key role in repair of UVB induced DNA damage. Our studies show that mice lacking the type I IFN receptor 1 (IFNAR1) had decreased repair of UVB induced CPD in the skin and increased immunosuppression. Regulation of type I IFNs has been well studied at the transcriptional level but there is a dearth of information on regulation at the post-transcriptional level. K-homology type regulatory splicing protein (KSRP) has been shown to regulate the production of type I IFNs, at the post-transcriptional level in response to viral infection, by promoting the decay of their mRNA. We have found that KSRP inhibits the repair of CPD in mouse skin and is highly expressed in human skin tumors compared to normal skin. We hypothesize that type I IFNs will repair UVB induced DNA damage and prevent tumor development in mice. These type I IFN mediated processes will be regulated by KSRP. To test our hypothesis, we will use mice, lacking IFNAR1, which is critical for signaling of type I IFNs, and mice lacking KSRP. Using these unique mouse models, we will be able to (1) Determine the mechanisms by which type I IFNs are produced after UVB induced DNA damage, the cell type that produces them, and the manner in which they repair the CPD formed after exposure to UVB radiation; (2) Dissect the mechanism of regulation of type I IFNs by KSRP, after UVB induced DNA damage; (3) Elucidate whether type I IFNs mediate development of UVB induced skin tumors and whether KSRP contributes to their regulation in this process.

摘要