Humanized Mouse Models for the p53 R72P SNP

p53 R72P SNP 人源化小鼠模型

• 批准号: 7996051
• 负责人: David G. Johnson
• 金额: $ 28.97万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7996051
• 关键词: Affect; Alleles; Amino Acids; Apoptosis; Apoptotic; Arginine; Bacterial Artificial Chromosomes; Basic Science; Biological; Cellular Stress; Codon Nucleotides; Conflict (Psychology); Data; Development; Disease; Disease susceptibility; Environmental Exposure; Epidemiologic Studies; Exons; Exposure to; Gene Expression Regulation; Gene Targeting; Genetic; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genomics; Genotype; Health; Human; Human Cell Line; Human Development; Human Genetics; Human Genome; In Vitro; Individual; Knock-out; Laboratory Study; Lead; Malignant Neoplasms; Mitochondria; Modeling; Modification; Molecular; Mus; Mutate; Mutation; Oncogenic; Patients; Physiological; Play; Positioning Attribute; Predisposition; Proline; Protein p53; Proteins; Resistance; Risk; Role; Single Nucleotide Polymorphism; Site; Skin Cancer; Stress; TP53 gene; Testing; Tissue Model; Tissues; Transgenic Mice; Translational Research; UV induced; Ultraviolet Rays; Uncertainty; Variant; base; cancer type; carcinogenesis; case control; embryonic stem cell; environmental agent; gain of function; homologous recombination; human disease; mouse model; mutant; novel; overexpression; research study; response; skin squamous cell carcinoma; temperature sensitive mutant; tool; tumor

DESCRIPTION (provided by applicant): Individuals exposed to the same environmental agent often respond differently due to additional factors such as genetics. Therefore, determining how human sequence variations (polymorphisms) influence the response to environmental exposures is key to understanding individual variability in disease susceptibility. The human p53 gene, which plays a critical role in the response to many cellular stresses, contains a common polymorphism that results in either an arginine (R) or proline (P) residue at position 72 of the p53 protein. Numerous epidemiological studies have associated this polymorphism with risk for developing various cancers and other diseases. However, different genotypes are associated with a predisposition for developing different cancers and in some cases there is conflicting data. Some laboratory studies suggest that the two p53 variants differ in their abilities to activate certain target genes while other studies suggest that the variants differ in their ability to induce apoptosis through a transcription-independent mechanism. Moreover, this polymorphism may affect the gain-of-function ability of mutant p53. A major problem with the interpretation of these functional studies is that all were done using artificial in vitro conditions and thus there is a critical need to model the R72P polymorphism in a way that is more physiologically relevant. This application is based on the hypothesis that the human p53 R72P polymorphism can be modeled in the mouse and that these models can be important tools for basic and translational research. Mouse models have been developed to study the role of specific mutations and sites of modification on p53, but no mouse model has been developed to study the R72P polymorphism. This may be because amino acid 72 is located in a region of human p53 that lacks homology to murine p53. To overcome this problem, we have used two different approaches to develop "humanized" mouse models for the p53 R72P polymorphism. Experiments proposed in this application will validate these mouse models with a focus on determining how the R72P polymorphism modulates apoptosis and skin cancer development. The long-term objective of this proposal is to use data from these mouse model studies to develop and test new hypothesis on the role of this p53 polymorphism in human health and disease. PUBLIC HEALTH RELEVANCE: Determining how small variations in the human genome (polymorphisms) influence the response to environmental exposures is key to understanding individual variability in disease susceptibility. Epidemiological studies suggest that a single nucleotide polymorphism (SNP) in the human p53 gene affects an individual's chances of developing various cancers but the underlying mechanism for this is not understood. This proposal seeks to use novel mouse models to study how this common p53 SNP modulates the development of human cancer and other environmentally related diseases.

描述（由申请人提供）：由于遗传等其他因素，暴露于相同环境因素的个体通常会产生不同的反应。因此，确定人类序列变异（多态性）如何影响对环境暴露的反应是了解疾病易感性个体差异的关键。人类 p53 基因在对许多细胞应激的反应中发挥着关键作用，它包含一个常见的多态性，导致 p53 蛋白的 72 位出现精氨酸 (R) 或脯氨酸 (P) 残基。许多流行病学研究已将这种多态性与患各种癌症和其他疾病的风险联系起来。然而，不同的基因型与患不同癌症的倾向相关，并且在某些情况下存在相互矛盾的数据。一些实验室研究表明，这两种 p53 变体激活某些靶基因的能力不同，而其他研究表明，这两种变体通过转录无关机制诱导细胞凋亡的能力不同。此外，这种多态性可能会影响突变体p53的功能获得能力。解释这些功能研究的一个主要问题是，所有研究都是在人工体外条件下完成的，因此迫切需要以更生理相关的方式对 R72P 多态性进行建模。该应用基于这样的假设：人类 p53 R72P 多态性可以在小鼠中建模，并且这些模型可以成为基础和转化研究的重要工具。已经开发出小鼠模型来研究 p53 上特定突变和修饰位点的作用，但尚未开发出小鼠模型来研究 R72P 多态性。这可能是因为氨基酸 72 位于人 p53 的一个区域，该区域与鼠 p53 缺乏同源性。为了克服这个问题，我们使用了两种不同的方法来开发 p53 R72P 多态性的“人源化”小鼠模型。本申请中提出的实验将验证这些小鼠模型，重点是确定 R72P 多态性如何调节细胞凋亡和皮肤癌的发展。该提案的长期目标是利用这些小鼠模型研究的数据来开发和测试有关 p53 多态性在人类健康和疾病中的作用的新假设。公共卫生相关性：确定人类基因组中的微小变异（多态性）如何影响对环境暴露的反应是了解疾病易感性个体差异的关键。流行病学研究表明，人类 p53 基因中的单核苷酸多态性 (SNP) 会影响个体患各种癌症的机会，但其潜在机制尚不清楚。该提案旨在使用新型小鼠模型来研究这种常见的 p53 SNP 如何调节人类癌症和其他环境相关疾病的发展。