Humanized Mouse Models for the p53 R72P SNP

描述（由申请人提供）：由于遗传等其他因素，暴露于相同环境因子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理解疾病易感性个体差异的关键。人类p53基因在许多细胞应激反应中起着至关重要的作用，它含有一种常见的多态性，导致p53蛋白的72位存在精氨酸(R)或脯氨酸(P)残基。许多流行病学研究已经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易感性有关，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变体在激活某些靶基因的能力上存在差异，而其他研究表明，这两种变体在通过转录不依赖机制诱导细胞凋亡的能力上存在差异。此外，这种多态性可能影响突变p53的功能获得能力。解释这些功能研究的一个主要问题是，所有这些研究都是在人工体外条件下完成的，因此迫切需要以一种更具有生理学相关性的方式来模拟R72P多态性。该应用程序基于人类p53 R72P多态性可以在小鼠中建模的假设，并且这些模型可以成为基础研究和转化研究的重要工具。已经建立了小鼠模型来研究特定突变和p53修饰位点的作用，但尚未建立小鼠模型来研究R72P多态性。这可能是因为氨基酸72位于人类p53的一个区域，与小鼠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。本应用程序中提出的实验将验证这些小鼠模型，重点确定R72P多态性如何调节细胞凋亡和皮肤癌的发展。这项提议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p53多态性在人类健康和疾病中的作用的新假设。

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.