Antioxidant Therapy for Ataxia Telangiectasia

描述（由申请人提供）：ATM（共济失调毛细血管扩张突变）杂合性似乎是癌症的风险因素。尽管BRCA 1和BRCA 2的患病率似乎很低，但由于在人群中的患病率高达1-5%，因此人群风险高于BRCA 1和BRCA 2的总和。我们推测，只有一些ATM杂合子的人患癌症的原因可能部分是由于这样一个事实，即人类群体在其他遗传癌症易感或保护因素以及营养因素方面差异极大，只有某些基因-基因和/或基因-营养相互作用可能导致癌症的最高风险。遗传不稳定性，特别是DNA缺失与癌症的病因学有关。ATM缺陷型纯合子患者和小鼠显示出癌症的高发病率，氧化应激的迹象和DNA缺失的频率升高，这是我们使用体内色素沉着测定发现的。该试验基于对由pun突变回复引起的被毛和眼睛上的黑点的定量。这种逆转通过缺失p基因内70 kb的内部重复而发生。我们还表明，ATMASRI错义突变纯合子以及杂合子小鼠显示DNA缺失频率升高。此外，我们已经表明，ATM纯合破坏突变小鼠中DNA缺失频率升高通过营养补充自由基清除剂N-乙酰半胱氨酸（NAC）完全恢复到野生型水平。GGT缺陷小鼠的谷胱甘肽水平较低，并显示出氧化应激的迹象。在目的1中，我们提出研究ATMASRI杂合子或纯合子小鼠与GGT缺陷一起是否显示协同升高的DNA缺失频率（基因-基因相互作用），在目的2中，我们提出测试营养补充NAC的ATMASRI纯合子和杂合子小鼠是否显示DNA缺失频率降低，以及补充促氧化剂BSO的小鼠是否显示缺失频率增加（基因营养相互作用）。在第三个目标中，将测试ATMASRI纯合子小鼠中升高的癌症频率是否可以通过使用抗氧化剂NAC（基因-营养相互作用）的化学预防来降低。对人类健康的影响可能包括，ATM患者以及杂合子人群（占人口的1-5%）与易受氧化应激影响的遗传或营养因素相结合，可能会增加患癌症的风险，而抗氧化剂的化学预防可能会降低这些遗传易感人群的癌症风险。

DESCRIPTION (provided by applicant): ATM (ataxia telangiectasia mutated) heterozygosity seems to be a risk factor for cancer. Even though the penetrance seems to be low, because of the high prevalence of 1-5% in the human population, the population risk is higher than for BRCA1 and BRCA2 together. We hypothesize that the reason why only some people heterozygous for ATM develop cancer may in part be due to the fact that the human population is extremely varied with regard to additional genetic cancer predisposing or protecting factors as well as nutrition factors and that only certain gene-gene and/or gene-nutrition interactions may lead to the highest risk for cancer. Genetic instability, in particular DNA deletions are involved in the etiology of cancer. ATM deficient homozygous patients and mice show a high incidence of cancer, signs of oxidative stress and an elevated frequency of DNA deletions which we found using an in vivo pigmentation assay. This assay is based on the quantification of black spots on fur and eyes resulting from reversion of the pun mutation. This reversion occurs by deletion of 70 kb of an internal duplication within the p gene. We have also shown that ATMASRI missense mutation homozygous as well as heterozygous mice show elevated frequencies of DNA deletions. In addition, we have shown that the elevated frequency of DNA deletions in ATM homozygous disruption mutant mice is completely reverted to wildtype levels by nutritional supplementation with the radical scavenger N-acetyl cysteine (NAC). GGT deficient mice have lower levels of glutathione and show signs of oxidative stress. In aim 1 we propose to investigate whether ATMASRI heterozygous or homozygous mice together with GGT deficiency show synergistically elevated frequencies of DNA deletions (gene-gene interactions), In aim 2 we propose to test whether ATMASRI homo and heterozygous mice nutritionally supplemented with NAC show reduced frequencies of DNA deletions and whether mice supplemented with the prooxidant BSO show an increased frequency of deletions (gene-nutrition interactions). It will be tested in the third aim whether the elevated frequency of cancer in ATMASRI homozygous mice can be reduced by chemoprevention with the antioxidant NAC (gene-nutrition interaction). Implications for human health may include that ATM patients as well as heterozygous people (1-5% of the human population) in combination with genetic or nutritional factors predisposing to a higher sensitivity to oxidative stress may show an increased risk for cancer, and that chemoprevention with antioxidants may reduce the cancer risk in such genetically predisposed people.