Does reducing Grb2 alter aging?

描述（由申请人提供）：Grb 2是一种衔接蛋白，在胰岛素和IGF-I受体下游发挥作用。Grb 2与She同种型结合并在胰岛素/IGF-1介导的促有丝分裂事件中起关键作用。有一些数据表明，降低Grb 2表达水平可能会减少与衰老相关的肿瘤进展并延长寿命。首先，Grb 2的表达增强加速了肿瘤的发展。相比之下，通过基因靶向降低Grb 2表达延缓了多瘤病毒中T抗原在整个动物中诱导的乳腺癌。此外，破坏p66 Shc（与Grb 2相互作用的She同种型之一）的基因表达，导致对氧化应激的抵抗力增加和寿命延长。最后，热量限制，这已被证明是决定性的和可重复的，以增加最大寿命，同时减弱年龄相关的病理，如肿瘤进展的发展，显着降低Grb 2的表达水平。基于这些发现，我们假设降低小鼠Grb 2的表达水平通过延迟肿瘤进展和增加对氧化应激的抵抗力来增加寿命。为了验证这一假设，我们提出了以下具体目标：1。确定减少Grb 2表达是否增强小鼠对氧化应激的抵抗力。2.确定降低Grb 2表达水平是否抑制小鼠肿瘤发生率。3.确定减少小鼠Grb 2表达是否会延长寿命。这些研究的结果将使我们能够确定Grb 2表达水平降低的小鼠是否是研究衰老的新型动物模型。

DESCRIPTION (provided by applicant): Grb2 is an adaptor protein that functions downstream of the insulin and IGF-I receptors. Grb2 binds to the She isoforms and plays a key role in insulin/IGF-l-mediated mitogenic events. There are some data suggesting that reducing Grb2 expression levels may decrease aging-associated tumor progression and extend lifespan. First, enhanced expression of Grb2 accelerates tumor development. In contrast, reducing Grb2 expression by gene targeting retards mammary carcinomas induced by polyomavirus middle T antigen in whole animals. Furthermore, disruption of the gene expression of p66Shc, one of the She isoforms that interacts with Grb2, leads to increased resistance to oxidative stress and extended lifespan. Finally, caloric restriction, which has been conclusively and reproducibly shown to increase maximum lifespan while attenuating the development of age-associated pathology such as tumor progression, significantly reduced the expression levels of Grb2. Based on these findings, we hypothesize that reducing the expression levels of Grb2 in mice increases lifespan by delaying tumor progression and increasing resistance to oxidative stress. To test this hypothesis, we propose the following Specific Aims: 1. To determine whether reducing Grb2 expression enhances resistance to oxidative stress in mice. 2. To determine whether reducing Grb2 expression levels inhibits tumor incidence in mice. 3. To determine whether reducing Grb2 expression in mice leads to extended lifespan. Results from these studies will allow us to determine if the mice with reduced levels of Grb2 expression are a novel animal model to study aging.