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.

尽管进行了深入的研究工作，但迄今为止，可以建立针对放射治疗的高级急性毒性的生物标志物预测。遵循当前的文献报道和自己的试点研究SMAD7的表达，Smad7是转化生长因子β信号通路的内源性自身抑制剂，似乎是一种有希望的方法。根据我们的观察，在放射化学疗法中在患者匹配的成纤维细胞中模拟了SMAD7的早期诱导与较低的临床急性毒性相吻合，该项目建议应解决以下问题：1）观察到的SMAD7如何诱导与整个转录型在纤维中的转录化学疗法的影响有关？ 2）鉴于（1）分别由特异性靶向的过表达和抑制SMAD7的最强笔录置入了（1）？ 3）辐射与SMAD7启动子活性相互作用以了解可变转录诱导的机制如何？ 4）是否有任何遗传遗传多态性调节内源性SMAD7转录？ 5）如何在CRISPR/CAS9技术设计的细胞模型中分析放射化学疗法引起的SMAD7转录变化的动态剂量时间效应？是否有建立的药物在此模型系统中显示出有效的SMAD7诱导？具体的目的是获取详细信息，以更好地理解放射治疗期间发生的SMAD7转录的相关性，并将相关发现应用于临床使用。该应用所基于的患者衍生成纤维细胞中临床毒性和转录效应在体内的直接关系是这种转化方法的特殊特征。在这方面，该提案的问题代表了床边的居民三明治的中间部分。然后，应在研究人员发起的试验（IIT）中对应用研究的主要结果进行测试，以评估临床相关性和可行性。