SMAD7 expression and radiotoxicity: Clarification of mechanisms for the observed correlation in fibroblasts with clinical toxicity and development of a cell model for evaluation of pharmacological interventions

SMAD7 表达和放射毒性：阐明成纤维细胞中观察到的与临床毒性相关性的机制，并开发用于评估药理干预的细胞模型

基本信息

批准号：
317556944
负责人：
Privatdozent Dr. Markus Schirmer
金额：
--
依托单位：
Institut für Humangenetik
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/317556944?language=en
关键词：
SMAD7 expression radiotoxicity Clarification mechanisms

项目摘要

Despite intensive research efforts no biomarkers predictive for higher grade acute toxicity by radiotherapy could be established for clinical use so far. Following current literature reports and own pilot investigations expression of SMAD7, the endogenous autoinhibitor of the transforming growth factor beta signalling pathway, appears as a promising approach. Based on our observation that early induction of SMAD7 when radiochemotherapy was simulated in patient-matched fibroblasts was coincident with lower clinical acute toxicity the following issues should be addressed by this project proposal: 1) How is the observed SMAD7 induction in relation to the effects of simulated radiochemotherapy on the entire transcriptome in fibroblasts? 2) Given the strongest transcripts indentified by (1) how are they affected by specifically targeted overexpression and suppression of SMAD7, respectively? 3) How are the mechanisms by which radiation interacts with SMAD7 promoter activity to understand variable transcription induction? 4) Are there any inherited genetic polymorphisms modulating endogenous SMAD7 transcription? 5) How are the dynamic dose-time effects for SMAD7 transcription changes induced by radiochemotherapy to be analyzed in a cellular model to be engineered by the CRISPR/Cas9 technology? Are there established pharmaceuticals showing effective SMAD7 induction in this model system? The specific aim is to get detailed information for better understanding of the relevance of SMAD7 transcription occurring during radiotherapy and to apply relevant findings for soon clinical use. The direct relationship detected between clinical toxicity and transcriptional effects ex vivo in patient-derived fibroblasts on which this application is based represent a special feature of this translational approach. In this regard, the issues of this proposal represent the middle part of a bedside-benach-bedside sandwich. The major results of the applied investigations should then be prospectively tested in an investigator-initiated trial (IIT) to evaluate clinical relevance and feasibility.

尽管进行了大量的研究工作，但迄今为止还没有建立可预测放疗引起的更高级别急性毒性的生物标志物用于临床。根据当前的文献报告和我们自己的初步研究，SMAD7（转化生长因子β信号通路的内源性自身抑制剂）的表达似乎是一种有前途的方法。根据我们的观察，在患者匹配的成纤维细胞中模拟放化疗时，SMAD7 的早期诱导与较低的临床急性毒性一致，该项目提案应解决以下问题：1）观察到的 SMAD7 诱导与放化疗的效果有何关系？对成纤维细胞整个转录组进行模拟放化疗？ 2）给定最强的转录本（1）它们分别如何受到特定目标的 SMAD7 过表达和抑制的影响？ 3) 辐射与 SMAD7 启动子活性相互作用的机制如何理解可变转录诱导？ 4)是否存在调节内源SMAD7转录的遗传性基因多态性？ 5) 如何在 CRISPR/Cas9 技术设计的细胞模型中分析放化疗诱导的 SMAD7 转录变化的动态剂量-时间效应？是否有已建立的药物在该模型系统中显示出有效的 SMAD7 诱导作用？具体目的是获得详细信息，以便更好地了解放疗期间发生的 SMAD7 转录的相关性，并将相关发现尽快应用于临床。在本应用所基于的患者来源的成纤维细胞中检测到的临床毒性和离体转录效应之间的直接关系代表了这种转化方法的一个特殊特征。在这方面，本提案的问题代表了床边-长凳-床边三明治的中间部分。然后应在研究者发起的试验（IIT）中对应用研究的主要结果进行前瞻性测试，以评估临床相关性和可行性。