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危险因素。尽管外显率似乎很低，但由于在人群中的高患病率为1-5%，因此人群风险高于BRCA1和BRCA2的总和。我们假设，为什么只有一部分人患有ATM杂合的原因可能部分是由于人类在额外的遗传癌症易感性或保护因素以及营养因素方面存在极大的差异，并且只有某些基因-基因和/或基因-营养相互作用可能导致最高的癌症风险。遗传不稳定，特别是DNA缺失与癌症的病因有关。我们在体内色素沉着试验中发现，ATM纯合子缺陷患者和小鼠表现出高癌症发病率、氧化应激迹象和DNA缺失频率升高。这种分析是基于定量的黑点在皮毛和眼睛产生的双关突变的逆转。这种逆转是通过p基因内部重复的70kb的缺失而发生的。我们还表明，ATMASRI错义突变纯合和杂合小鼠显示DNA缺失的频率升高。此外，我们已经证明，通过营养补充自由基清除剂n -乙酰半胱氨酸（NAC）， ATM纯合破坏突变小鼠的DNA缺失频率升高完全恢复到野生型水平。缺乏GGT的小鼠谷胱甘肽水平较低，并表现出氧化应激的迹象。在目标1中，我们建议研究GGT缺乏的ATMASRI杂合或纯合小鼠是否会协同提高DNA缺失的频率（基因-基因相互作用），在目标2中，我们建议测试营养补充NAC的ATMASRI同型和杂合小鼠是否会降低DNA缺失的频率，以及补充促氧化剂BSO的小鼠是否会增加缺失的频率（基因-营养相互作用）。在第三个目标中，我们将测试ATMASRI纯合子小鼠的癌症发病率升高是否可以通过抗氧化剂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%），加上易受氧化应激敏感性较高的遗传或营养因素，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类易受氧化应激影响人群的癌症风险。

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.