权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

重新连接 miRNA-MDM2-p53 网络以重新激活 p53 功能

基本信息

批准号：
8364777
负责人：
Leonidas Bleris
金额：
$ 16.64万
依托单位：
UNIVERSITY OF TEXAS DALLAS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8364777
关键词：
Address Apoptosis Basic Cancer Research Biochemical Biological Sciences Budgets Cell Cycle Arrest Cell physiology Cells Cellular Stress Response Complex Computer Simulation Coupled DNA Detection Development Diagnosis Disease Doctor of Philosophy Drug Delivery Systems Electrical Engineering Engineering Environmental Risk Factor Feedback Genes Genome Stability Health Heart Homeostasis Human Individual Intervention Knowledge Lead Life Light MDM2 gene Malignant Neoplasms Mathematics Medical Medicine Methods MicroRNAs Modality Molecular Pathway interactions Patients Play Principal Investigator Process Property Protein p53 Proteins RNA Reaction Regulation Research Resolution Role Signal Pathway Signal Transduction Signal Transduction Pathway Stress System Systems Biology Time Training Treatment-Related Cancer Tumor Suppression Vesicle Work base biological adaptation to stress cancer initiation cancer prevention cancer therapy design environmental change experience in vivo inhibitor/antagonist innovation insight laboratory facility mathematical model meetings models and simulation molecular scale novel prevent research study response senescence sensor small molecule synthetic biology theories tool transcription factor tumor

项目摘要

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. PUBLIC HEALTH RELEVANCE: We propose novel theoretical methods to examine the relationship between p53-MDM2 and microRNAs, and experimentally rewire the miRNA-p53-MDM2 core. Advances in understanding of the interplay between p53 response and miRNAs regulation can provide new insight to existing treatment modalities. Importantly, our work will aim to redefine medical strategies, introducing closed-loop molecular interventions in the treatment of p53-dependent human cancers.

描述（由申请人提供）：信号网络检测、处理和特异性反应各种应激信号的能力是活细胞的关键特性。表征对于这些通常极其复杂的信号转导途径，一种有前途的方法是使用定量实验与建模和模拟协同。我们专注于p53应激反应的网络，p53除了对疾病和正常生活的许多其他方面的贡献外，还在癌症的发生和预防中发挥着关键作用。位于复杂调节的核心是MDM 2对p53的自动调节反馈，MDM 2是p53的关键负调节因子。由于大多数人类恶性肿瘤关闭了p53肿瘤抑制反应以存活，因此p53和MDM 2是癌症治疗中最有希望的药物干预靶点。与此同时，microRNAs（miRNAs）已成为几乎所有细胞过程中的关键调控因子，最近的研究表明，miRNAs与p53-MDM 2核心有直接的相互作用。可以肯定的是，由miRNAs和p53-MDM 2形成的偶联通路在细胞健康中起着重要作用。我们建议开发新的方法来从理论上评估p53-MDM 2和miRNA之间的相互作用，并在实验上重新连接miRNA-p53-MDM 2网络。我们提出了新的分子电路的实验实施工程，以响应microRNA引入闭环反馈控制，以恢复p53功能。我们相信，我们的建议可以为治疗p53依赖性人类癌症的医学策略提供新的见解。公共卫生相关性：我们提出了新的理论方法来研究p53-MDM 2和microRNA之间的关系，并通过实验重新连接miRNA-p53-MDM 2核心。对p53反应和miRNAs调控之间相互作用的理解的进展可以为现有的治疗方式提供新的见解。重要的是，我们的工作将旨在重新定义医疗策略，在p53依赖性人类癌症的治疗中引入闭环分子干预。