Humanized Mouse Models for the p53 R72P SNP

描述（由申请人提供）：此申请是对NOT-OD-09-058的回应，NIH宣布为竞争性修订申请提供恢复法案资金。由于遗传等其他因素的影响，暴露于同一环境因素的不同个体往往会产生不同的反应。因此，了解人类序列变异（多态性）如何影响对环境暴露的反应是理解疾病易感性的个体差异的关键。p53肿瘤抑制因子在许多细胞应激反应中起关键作用，包括暴露于遗传毒性化学物质和辐射。MDM2是p53的关键调节因子，它能够对p53活性的增加做出反应，并使p53失活和降解。p53和MDM2基因都含有常见的单核苷酸多态性（snp），与某些人类癌症的风险增加有关。在p53的情况下，非同义SNP导致p53蛋白72位的精氨酸(R)或脯氨酸(P)残基。实验室研究表明，两种p53变体具有不同的生物学特性，特别是在诱导细胞凋亡的能力方面。在MDM2的情况下，SNP位于内含子1调控序列（G或T位于309位）内，并影响MDM2的表达水平。与SNP309的T等位基因相比，G在SNP309上的存在导致MDM2的表达增加，p53的反应性降低。最初的申请（R01 ES015587）是基于使用p53 R72P多态性的新型小鼠模型来研究该SNP在调节鳞状细胞癌发展中对环境和致癌应激的反应中的作用。在这一竞争性修订中，我们建议扩大我们的研究，包括MDM2 SNP309多态性的新型小鼠模型。这些小鼠模型是第一个模拟自然发生的人类多态性的模型，将使我们能够在分子水平上研究这些snp在高度生理环境下调节应激反应和癌症发展中的作用。此外，通过将MDM2 SNP309小鼠模型纳入这些研究，可以研究p53和MDM2变体之间的基因-基因相互作用。为了验证我们的小鼠模型在模拟人类疾病方面的有效性，我们还将进行分子流行病学研究，以确认类似的基因-基因相互作用也会调节人类癌症的发展。

DESCRIPTION (provided by applicant): This application is in response to NOT-OD-09-058, NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. Different individuals exposed to the same environmental agent often respond differently due to additional factors such as genetics. Therefore, understanding how human sequence variations (polymorphisms) influence the response to environmental exposures is key to understanding individual variability in disease susceptibility. The p53 tumor suppressor plays a critical role in the response to many cellular stresses, including exposure to genotoxic chemicals and radiation. MDM2 is a critical regulator of p53 through its ability to respond to increased p53 activity and target p53 for inactivation and degradation. Both the p53 and MDM2 genes contain common single nucleotide polymorphisms (SNPs) that are associated with increased risk for some human cancers. In the case of p53, a non-synonymous SNP results in either an arginine (R) or proline (P) residue at position 72 of the p53 protein. Laboratory studies demonstrate that the two p53 variants have different biological properties, particularly in their abilities to induce apoptosis. In the case of MDM2, the SNP lies within intron 1 regulatory sequences (G or T at position 309) and affects the expression levels of MDM2. The presence of G at SNP309 results in increased expression of MDM2 and decreased p53 responsiveness compared to the T allele of SNP309.The original application (R01 ES015587) was based on the use of novel mouse models for the p53 R72P polymorphism to study the role of this SNP in modulating the response to environmental and oncogenic stresses in squamous cell carcinoma development. In this competitive revision, we propose to expand our studies to include novel mouse models for the MDM2 SNP309 polymorphism. These mouse models are the first to mimic naturally occurring human polymorphisms and will allow us to examine at the molecular level the role of these SNPs in modulating the response to stress and cancer development in a highly physiological setting. Moreover, by including the MDM2 SNP309 mouse models into these studies, gene-gene interactions between the p53 and MDM2 variants can be studied. To validate the usefulness of our mouse models in mimicking human disease we will also perform molecular epidemiological studies to confirm that similar gene-gene interactions also modulate cancer development in humans. PUBLIC HEALTH RELEVANCE: Genetic differences among individuals play a major role in determining the response to environmental exposures and risk for developing disease. The goal of this project is to use novel mouse models to study how two common human gene variants interact with each other to modulate the development of squamous cell carcinoma of the skin and head & neck.