Humanized Mouse Models for the p53 R72P SNP

p53 R72P SNP 人源化小鼠模型

• 批准号: 8207922
• 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/8207922
• 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）：暴露于同一环境药物的个人通常由于遗传学等其他因素而反应不同。因此，确定人类序列变化（多态性）如何影响对环境暴露的反应是了解疾病敏感性的个体变异性的关键。人p53基因在对许多细胞应激的反应中起着至关重要的作用，其中包含一种常见的多态性，在p53蛋白的第72位处导致精氨酸（R）或脯氨酸（P）残基。许多流行病学研究已将这种多态性与发展各种癌症和其他疾病的风险相关联。但是，不同的基因型与开发不同癌症的易感性有关，在某些情况下，数据矛盾。一些实验室研究表明，两种p53变体的激活某些靶基因的能力有所不同，而其他研究表明，它们通过独立的转录机制诱导凋亡的能力有所不同。此外，这种多态性可能会影响突变体p53的功能获得能力。这些功能研究的解释的一个主要问题是，所有问题都是使用人工体外条件进行的，因此，迫切需要以更相关的方式对R72p多态性进行建模。该应用基于以下假设：人类p53 R72p多态性可以在小鼠中建模，并且这些模型可以是基本和转化研究的重要工具。已经开发了小鼠模型来研究特定突变和修饰位点在p53上的作用，但是尚未开发小鼠模型来研究R72p多态性。这可能是因为氨基酸72位于与鼠p53同源的人p53区域。为了克服这个问题，我们使用了两种不同的方法来为p53 R72p多态性开发“人性化”小鼠模型。本应用中提出的实验将验证这些小鼠模型，重点是确定R72p多态性如何调节凋亡和皮肤癌的发展。该提案的长期目标是使用这些小鼠模型研究中的数据来开发和检验有关该p53多态性在人类健康和疾病中作用的新假设。公共卫生相关性：确定人类基因组（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。流行病学研究表明，人p53基因中的单个核苷酸多态性（SNP）会影响一个人发展各种癌症的机会，但是对此的基本机制却尚不清楚。该提案试图使用新颖的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与环境相关的疾病的发展。