Humanized Mouse Models for the p53 R72P SNP

p53 R72P SNP 人源化小鼠模型

• 批准号: 7812646
• 负责人: David G. Johnson
• 金额: $ 69.3万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2012-03-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7812646
• 关键词: Affect; Alleles; Apoptosis; Apoptotic; Arginine; Biological; Case-Control Studies; Cellular Stress; Chemicals; Development; Disease; Disease susceptibility; Environmental Exposure; Epidemiologic Studies; Exposure to; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Goals; Head and neck structure; Human; Individual; Introns; Laboratory Study; MDM2 gene; Malignant Neoplasms; Mediating; Molecular; Oncogenic; Pathway interactions; Patients; Physiological; Play; Positioning Attribute; Proline; Property; Protein p53; Radiation; Recovery; Risk; Role; Single Nucleotide Polymorphism; Skin; Squamous cell carcinoma; Stress; TP53 gene; Testing; United States National Institutes of Health; Variant; base; environmental agent; gene interaction; human disease; mouse model; novel; overexpression; public health relevance; response; skin squamous cell carcinoma; tumorigenesis; ultraviolet irradiation

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.

描述（由申请人提供）：此申请是针对NOT-OD-09-058的响应，NIH宣布为竞争性修订申请提供恢复法案资金。由于遗传学等其他因素，接触相同环境药物的不同个体通常会有所不同。因此，了解人类序列变化（多态性）如何影响对环境暴露的反应是了解疾病易感性的个体变异性的关键。 p53肿瘤抑制剂在对许多细胞应激的反应中起着至关重要的作用，包括暴露于遗传毒性化学物质和辐射。 MDM2是p53的关键调节剂，其能够响应增加的p53活性并靶向p53以造成失活和降解。 p53和MDM2基因都包含常见的单核苷酸多态性（SNP），与某些人类癌的风险增加有关。在p53的情况下，非同义性SNP会导致p53蛋白位置72处的精氨酸（R）或脯氨酸（P）残基。实验室研究表明，这两个p53变体具有不同的生物学特性，尤其是它们诱导凋亡的能力。在MDM2的情况下，SNP位于内含子1调节序列（位置309处的G或T）中，并影响MDM2的表达水平。与SNP309的T等位基因相比，SNP309处G的存在导致MDM2的表达增加和p53的反应性降低。原始应用（R01 ES015587）是基于对p53 R72P多形态p53 R72P多态性的新型鼠标模型的使用，以调整SNP对环境和孔子的响应的作用，以调节环境和孔子的响应。在这种竞争性的修订中，我们建议将研究扩展到包括MDM2 SNP309多态性的新型小鼠模型。这些小鼠模型是第一个模仿自然存在的人类多态性的模型，并将使我们能够在分子水平上检查这些SNP在高度生理环境中调节对压力和癌症发展的反应中的作用。此外，通过将MDM2 SNP309小鼠模型包括在这些研究中，可以研究p53和MDM2变体之间的基因基因相互作用。为了验证小鼠模型在模仿人类疾病中的实用性，我们还将进行分子流行病学研究，以确认类似的基因 - 基因相互作用还可以调节人类的癌症发展。 公共卫生相关性：个体之间的遗传差异在确定对环境暴露和发展疾病风险的反应方面发挥了重要作用。该项目的目的是使用新颖的小鼠模型研究如何相互相互作用，以调节皮肤和头部颈部鳞状细胞癌的发展。