Does reducing Grb2 alter aging?

描述(申请人提供)：Grb2是一种接头蛋白，作用于胰岛素和IGF-I受体下游。Grb2与SHE亚型结合，在胰岛素/胰岛素样生长因子-L介导的有丝分裂过程中发挥关键作用。有一些数据表明，降低Grb2的表达水平可能会减缓与衰老相关的肿瘤进展，延长寿命。首先，Grb2的增强表达加速了肿瘤的发展。相反，通过基因靶向降低Grb2的表达可以延缓多瘤病毒中T抗原在整个动物体内诱导的乳腺癌。此外，与Grb2相互作用的SHE亚型之一p66Shc的基因表达被破坏，导致对氧化应激的抵抗力增强，寿命延长。最后，卡路里限制显著降低了Grb2的表达水平，这已被确凿地和重复地证明可以延长最长寿命，同时减缓与年龄相关的病理变化，如肿瘤进展。基于这些发现，我们假设降低小鼠Grb2的表达水平通过延缓肿瘤进展和增强对氧化应激的抵抗力来延长寿命。为了验证这一假设，我们提出了以下具体目标：1.确定减少Grb2表达是否提高了小鼠对氧化应激的抵抗力。2.确定降低Grb2的表达水平是否能抑制小鼠肿瘤的发生。3.确定减少Grb2的表达是否能延长小鼠的寿命。这些研究的结果将使我们能够确定Grb2表达水平降低的小鼠是否是研究衰老的新动物模型。

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.