Based excision repair deficiency, folate and GI cancer

基于切除修复缺陷、叶酸和胃肠道癌症

基本信息

批准号：
7337375
负责人：
AHMAD R HEYDARI
金额：
$ 19.44万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-30 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7337375
关键词：
1,2-Dimethylhydrazine 2-nitropropane APC gene Address Adenocarcinoma Affect Aging Alkylation Alzheimer&apos s Disease Animal Model Animals Appearance Area Base Excision Repairs Cancer-Predisposing Gene Cancerous Carcinogen exposure Cardiovascular Diseases Chromosomal Instability Colon Congenital Abnormality DNA DNA Damage DNA Methylation DNA Repair DNA Single Strand Break DNA-Directed DNA Polymerase Data Development Down-Regulation Environmental Risk Factor Enzymes Event Excision Excision Repair Exons Folate Folic Acid Deficiency Food Interactions Frequencies Future Genes Genetic Polymorphism Genetic Transcription Genus Cola Goals Grant Health Human Individual Intervention Lesion Literature Liver Lymphoma Malignant - descriptor Malignant Neoplasms Measures Modeling Molecular Mus Mutation Names Nucleotides Numbers Outcome Pathology Pathway interactions Penetrance Phenotype Population Precipitating Factors Predisposition Process Proteins Public Health Rate Regulation Relative (related person)Research Design Research Personnel Research Project Grants Risk Risk Factors Role Site Supplementation TP53 gene Testing Time Tissues Transact Uracil Weight-Bearing state base cancer risk carcinogenesis colon carcinogenesis design high throughput screening insight micronucleus modifiable risk neoplastic novel pol genes programs promoter protective effect repaired research study response synergism tool tumor tumor progression tumorigenesis

项目摘要

Folate deficiency is an important public health concern as defined by its role in the development of many health problems, including birth defects, cardiovascular disease, Alzheimer's disease and cancer. A putative role for folate in protecting from cancer is convincingly suggested in both human and animal studies. We suggest that the mechanism by which folate deficiency increases cancer risk is by reducing the ability to repair damaged DMA. This is supported by a large body of experimental evidence demonstrating an accumulation of DNA damage, which suggests that an inability to repair this damage occurs in response to folate deficiency. Our hypothesis is that the accumulation of DNA damage, preneoplastic lesions and tumors caused by folate deficiency and carcinogen exposure will be accelerated by loss of p-pol, the rate limiting enzyme in base excision repair (BER) pathway. We have developed a BERdeficient animal model that expresses a phenotype of cancer susceptibility and reduced DNA damage threshold. We propose that low levels of folate induce BER deficiency by overwhelming the pathway. In an animal model deficient in BER, the resulting damage may so overburden the pathway that BER becomes ineffectual. The Specific Aims of this proposal are: 1) To determine the sensitivity of a BER deficient animal to folate deficiency; 2) To determine the sensitivity of a BER deficient animal to oxidative and alkylation damage when folate is deficient; 3) To evaluate whether BER deficiency accelerates the induction of preneoplastic lesions induced by DMH and 2-NP; and 4) To determine whether BER deficiency accelerates the induction of tumors caused by DMH and 2-NP when folate is deficient. The specific aims are designed to allow us to identify the precipitating factors in the development of tumors, and the impact that folate and BER deficiency have in these processes. If we find that cancer risk is modifiable in an animal model with BER deficiency, then development of a high throughput screening tool to identify individuals with reduced BER capacity would allow caretakers to identify individuals at risk, and provide an intervention i.e., folate supplementation.

叶酸不足是其在许多人的发展中的作用所定义的重要公共卫生问题健康问题，包括先天缺陷，心血管疾病，阿尔茨海默氏病和癌症。假定的在人类和动物研究中，令人信服地提出了叶酸在保护癌症中的作用。我们表明叶酸不足增加癌症风险的机制是通过降低能力修复受损的DMA。这是由大量的实验证据支持的 DNA损伤的积累，这表明无法修复这种损害是为了响应于叶酸不足。我们的假设是DNA损伤的积累，核肿瘤病变和由叶酸缺乏和致癌物暴露引起的肿瘤将通过p-pol的损失加速基础切除修复（BER）途径中的速率限制酶。我们已经开发了一种伯德动物表达癌症敏感性和DNA损伤阈值降低的模型。我们建议低水平的叶酸通过压倒途径来诱导BER缺乏症。在动物模型中缺乏贝尔，造成的损害可能使途径超重，以至于Ber变得无效。具体该提案的目的是：1）确定不足动物对卵巢缺乏的敏感性； 2）到确定叶酸为氧化和烷基化损伤的BER不足动物的敏感性不足； 3）评估BER缺乏是否会加速诱导的肿瘤性病变由DMH和2-NP; 4）确定BER缺乏是否会加速引起的肿瘤的诱导当叶酸不足时，DMH和2-NP。具体目标旨在使我们能够确定肿瘤发育中的促成因素，以及叶酸和BER缺乏的影响这些过程。如果我们发现癌症风险在具有BER缺乏症的动物模型中可以改变，那么开发高吞吐量筛查工具以识别降低的BER容量的人允许看护人识别有危险的人，并提供干预措施，即补充叶酸。