Rewiring the miRNA-MDM2-p53 network to reactivate p53 function

描述(由申请人提供)：信号网络检测、处理和反应各种应激信号的能力是活细胞的关键特性。刻画 这些通常是压倒性的复杂的信号转导途径，一个有前途的方法是使用定量实验与建模和模拟相结合。我们专注于P53应激反应的潜在网络，P53除了对疾病和正常生活的许多其他方面做出贡献外，还在癌症的启动和预防中发挥关键作用。处于错综复杂的调控的核心是MDM2对p53的自动调节反馈，MDM2是p53的关键负调控因子。由于大多数人类恶性肿瘤关闭了p53的肿瘤抑制反应以求生存，P53和MDM2是癌症治疗中最有希望的药物干预靶点之一。与此同时，microRNAs(MiRNAs)已经成为几乎每一个细胞过程中的关键调控角色，最近有趣的研究表明，miRNAs与p53-MDM2核心有直接的相互作用。可以肯定的是，由miRNAs和P53-MDM2形成的耦合通路在细胞健康中发挥着基础作用。我们建议开发新的方法来从理论上评估p53-MDM2和miRNAs之间的相互作用，并在实验上重新连接miRNA-p53-MDM2网络。我们提出了对microRNAs作出反应的新型分子电路的实验实现，引入了闭环反馈控制来恢复P53功能。我们相信，我们的建议可以为治疗依赖于P53的人类癌症的医学策略提供新的见解。

DESCRIPTION (provided by applicant): The ability of signaling networks to detect, process, and react specifically to various stress signals is a key property of living cells. To characterize these oftentimes overwhelmingly complex signal transduction pathways, one promising approach is to use quantitative experiments in synergy with modeling and simulations. We focus on the network underlying the stress response of p53, a pivotal player in cancer initiation and prevention aside from its contribution to numerous other aspects of disease and normal life. Lying at the heart of intricate regulations is the autoregulatory feedback of p53 by MDM2, a critical negative regulator of p53. As most human malignancies shut down the p53 tumor-suppressing responses to survive, p53 and MDM2 are of the most promising targets for drug intervention in cancer therapy. Meanwhile, microRNAs (miRNAs) have emerged as a key regulatory player in nearly every cellular process and intriguingly recent studies show that miRNAs have direct interactions with the p53-MDM2 core. It is safe to assume that the coupled pathways formed by miRNAs and p53-MDM2 play a fundamental role in cellular health. We propose to develop novel methods to theoretically assess the interactions between p53-MDM2 and miRNAs, and experimentally rewire the miRNA-p53-MDM2 network. We propose the experimental implementation of novel molecular circuits engineered to respond to microRNAs introducing closed-loop feedback control to revive the p53 function. We believe that our proposal can provide new insight to medical strategies in the treatment of p53-dependent human cancers.