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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：
10673138
负责人：
Craig A Elmets
金额：
$ 18.56万
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/10673138
关键词：
Adverse effects Alleles Anthracenes 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 Economic Burden Epitopes Exposure to 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 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 Testing 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 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.

摘要阳光是人类接触的主要环境因素。虽然它具有良好的效果（例如，维生素D的代谢，生命所需的能量），慢性过度暴露于紫外线部分导致DNA 损伤、皮肤过早老化、免疫抑制和非黑色素瘤皮肤癌（NMSC）（即，皮肤鳞状细胞癌和基底细胞癌）。仅在美国，就有超过500万新的NMSC接受治疗，年虽然这些恶性肿瘤的死亡率很低，但总体社会经济负担超过80亿美元每年。由于这个问题的临床意义，人们对识别紫外线辐射发挥其生物效应的机制以及预防其对健康不利影响的方法。紫外线诱发的皮肤癌具有高度免疫原性。此外，大约90%的人类SCC和50%的 BCC在p53肿瘤抑制基因中具有突变。紫外线照射与免疫原性的关系诱导的皮肤癌和p53突变是一个未探索的研究领域。这提供了理由用于针对p53突变的疫苗接种，以评估其预防紫外线辐射不良影响的能力。我们假设针对突变型p53免疫将导致产生CD 8 + T细胞，产生IFN-γ，这大大减少了产生免疫应答的突变，反过来，减少这种形式的辐射能的致癌作用。我们将通过首先确定通过评估p53的免疫原性突变表位在体外和体内刺激T细胞来源的免疫原性表位的能力，细胞因子和细胞介导的免疫应答。免疫程序将在疫苗接种小鼠，以观察其在预防UV诱导的p53突变中的功效，指导和减少由这些突变引起的紫外线诱导肿瘤的发生率。的最终目标这些研究将评估突变型p53疫苗接种是否可以预防UV诱导的肿瘤。