Imaging and Characterizating Stress responses in vivo with p21 Reporter Mice

化疗的全部潜力在实践中可能会受到毒副作用的限制。因此，战略或 在选择性地保护正常细胞而不是癌细胞方面有效的干预措施预计将 增加化疗的治疗窗口和临床疗效。出版的文学作品 表明短期停滞的小鼠可以免受高剂量依托泊苷的保护 杀死它们的哺乳后代。此外，携带突变的肿瘤细胞会导致结构性激活 PI3K途径已被证明在生长过程中对限制饮食的反生长效应不敏感 作为小鼠的异种移植。因此，禁食可能通过保护正常的 细胞，但不是癌细胞，来自化疗的毒性作用，临床试验目前正在进行中 测试化疗前或化疗期间禁食是否能减少癌症的相关副作用 病人。然而，对介导差异反应的分子机制知之甚少。 正常细胞与癌细胞相比，可短期饥饿。使用经过改造的报告鼠标 从内源p21启动子表达萤火虫荧光素酶，我们观察到p21的有效诱导 对短期停滞的反应。有趣的是，这发生在代谢器官和p21中。 这也是第一次观察到神经元的表达，特别是下丘脑中调节 新陈代谢。我们的初步研究还表明，p21可以保护细胞免受dna损伤。 伊立替康是一种拓扑异构酶1抑制剂，临床上用于治疗某些类型的癌症。因此，实验 在本申请中提出的将(1)确定短期饥饿诱导p21表达是否具有保护作用 从大剂量化疗和电离辐射对小鼠的致死效应，(2)识别信号 负责激活p21表达以应对短期饥饿的途径(S)和(3)决定 如果短期停药能保护小鼠，但不能保护在这些小鼠中生长的PTEN缺陷性前列腺癌，那么 化疗和放射治疗。

The full potential of chemotherapy can be limited in practice by toxic side effects. Therefore, strategies or interventions that are effective in selectively protecfing normal cells, but not cancer cells, are predicted to increase the therapeutic window and clinical effectiveness of chemotherapy. Published literature demonstrates that mice subjected to short-term stan/ation are protected from high doses of etoposide that kill their fed littermates. In addition, tumor cells carrying mutations that cause constitutive activation of the PI3K pathway have been shown to be insensitive to the anti-growth effects of dietary restriction when grown as xenografts in mice. Thus, fasting may enhance the effectiveness of chemotherapy by protecting normal cells, but not cancer cells, frcim the toxic effects of chemotherapy and clinical trials are currently being conducted to test whether fasting prior to or during chemotherapy reduces associated side-effects in cancer patients. However, little is known about the molecular mechanisms mediating the differential response of normal cells compared with cancer cells to short-term starvation. Using a reporter mouse engineered to express firefly luciferase from the endogenous p21 promoter, we observe a potent induction of p21 expression in response to short-term stan/ation. Interestingly, this occurs in metabolic organs and p21 expression was also observed, forthe first time, in particular neurons ofthe hypothalamus that regulate metabolism. Our preliminary studies also demonstrate that p21 protects cells from the DNA damaging effects of irinotecan, a topoisomerase 1 inhibitor used clinically to treat certain types of cancer. Thus, experiments proposed in this applicafion will (1) determine if induction of p21 expression by short-term starvation protects mice from the lethal effects of high dose chemotherapy and ionizing radiation, (2) identify the signaling pathway(s) responsible for activating p21 expression in response to short-term starvation and (3) determine if short-term stan/ation protects mice, but not PTEN-deficient prostate cancers growing in these mice, from chemotherapy and radiation therapy.