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UV Photodamage to the Skin: Prevention by Mutant p53 Immunization

皮肤紫外线光损伤：通过突变 p53 免疫预防

基本信息

批准号：
10528677
负责人：
Craig A Elmets
金额：
$ 22.28万
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：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10528677
关键词：
Adverse effects Alleles Antigens Area Aromatic Polycyclic Hydrocarbons Basal Cell Basal cell carcinoma Biological CD8-Positive T-Lymphocytes Cancer Etiology Cancer Vaccines Chronic Clinical Country Cutaneous DNA Damage Development Epitopes Future Generations Goals Growth and Development function Health Health Professional Human Immune Immune response Immunity Immunization Immunize Immunologic Surveillance Immunosuppression In Vitro Incidence Induced Mutation Interferon Type II Interferons Investigation Life Malignant Neoplasms Measures Messenger RNA Methods Modeling Mus Mutation Oncogenes Peptides Premature aging syndrome Prevention Prevention approach Procedures Protocols documentation Radiation induced damage Recommendation Skin Skin Aging Skin Cancer Skin Carcinoma Skin Neoplasms Squamous Cell Squamous cell carcinoma Sunlight Sunscreening Agents System T-Lymphocyte TP53 gene Techniques The Sun Tumor Suppressor Genes UV Radiation Exposure UV induced Ultraviolet Rays Vaccinated Vaccination Vaccines Vitamin D antigen-specific T cells antitumor effect carcinogenicity cell mediated immune response clinically significant cytokine dimethylbenzanthracene environmental agent experimental study exposed human population hazard immunogenic immunogenicity in vivo interest mortality mouse development mouse model mutant peptide vaccination photoprotection prevent skin cancer prevention skin damage skin squamous cell carcinoma socioeconomics sun damage tanning booths tumor tumorigenesis ultraviolet ultraviolet irradiation vaccine evaluation vitamin metabolism

项目摘要

ABSTRACT Sunlight is the major environmental agent to which humans are exposed. Although it has beneficial effects (e.g. metabolism of vitamin D, energy necessary for life), chronic overexposure to the ultraviolet portion causes DNA damage, premature aging of the skin, immunosuppression and non-melanoma skin cancers (NMSCs) (i.e. cutaneous squamous cell and basal cell carcinomas). In the U.S. alone >5 million new NMSCs are treated each year. Though mortality from these malignancies is low, the overall socioeconomic burden exceeds $8 billion annually. Because of the clinical significance of the problem, there has been intense interest in identifying mechanisms by which UV radiation exerts its biologic effects and methods to prevent its adverse health effects. UV-induced skin cancers are highly immunogenic. In addition, approximately 90% of human SCCs and 50% of BCCs have mutations in the p53 tumor suppressor gene. The relationship between the immunogenicity of UV- induced skin cancers and mutations in p53 is an unexplored area of investigation. This provides the rationale for vaccinating against p53 mutations to evaluate its capacity to prevent the adverse effects of UV radiation. We hypothesize that immunization against mutant p53 will result in the generation of CD8+ T-cells that preferentially produce IFN-γ, which greatly reduce the mutations to which the immune response was generated, and, in turn, reduce the carcinogenic effects of this form of radiant energy. We will examine this issue by first identifying immunogenic mutant epitopes of p53 by assessing their ability in vitro and in vivo to stimulate T-cell-derived cytokines and a cell-mediated immune response in mice. The immunization procedure will be evaluated in vaccination mice for its efficacy in preventing UV-induced p53 mutations to which the immune response is directed and in reducing the incidence of UV-induced tumors caused by those mutations. The ultimate goal of these studies will be to assess whether UV-induced tumors can be prevented by mutant p53 vaccination.

摘要