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The funktionality of DNA damage response pathmays in mammalian somatic stem cells and their role in oncogenic transformation, survival and differentiation

DNA损伤反应途径的功能可能发生在哺乳动物体干细胞中及其在致癌转化、存活和分化中的作用

基本信息

批准号：
131830284
负责人：
Dr. Leonid Schneider
金额：
--
依托单位：
Campus IFOM-IEO
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2009
资助国家：
德国
起止时间：
2008-12-31 至 2012-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/131830284?language=en
关键词：
funktionality DNA damage response pathmays

项目摘要

Somatic stem cells ensure tissue homeostasis through their two main capabilities: self renewal and differentiation. DNA damage in stem cells has been implicated in tumourigenesis and ageing. The functionality of molecular DNA damage response (DDR) pathways is thought to be decisive for the elimination of potentially cancerous cells through apoptotic cell death or senescence, with decreasing tissue homeostasis and ageing as side effects. Presently, DDR has been hardly addressed in tissue-specific stem cells, largely due to their poor accessibility. One recently established in vitro stem cell model are the neuronal stem cells (NSC). NSC cultures are homogenous and offer advantages of fast and abundant in vitro propagation. This project would elucidate for the first time the biological properties of stem cells by addressing the functionality of DDR pathways and their role in tumour suppression and tissue homeostasis, since emerging evidence suggests an involvement of the DDR factors also in differentiation processes. We intend to elucidate the roles of DDR kinase ATM and other DDR factors in stem cell survival and differentiation. Also, we would like to contribute to the research of cancer origins by asking whether expression of glyoblastoma-related oncogenes in NSC vs. their terminally differentiated descendants leads to senescence, apoptosis, transformation or de-differentiation.

体细胞通过自身更新和分化这两种主要功能来保证组织的动态平衡。干细胞中的DNA损伤与肿瘤的发生和衰老有关。分子DNA损伤反应(DDR)通路的功能被认为是通过凋亡细胞死亡或衰老来消除潜在的癌细胞的决定性因素，其副作用是减少组织内环境的稳定和衰老。目前，DDR很难在组织特异性干细胞中得到解决，这主要是因为它们很难获得。最近建立的一种体外干细胞模型是神经干细胞(NSC)。神经干细胞培养同源，具有快速、丰富的体外增殖优势。该项目将首次阐明干细胞的生物学特性，通过解决DDR通路的功能及其在肿瘤抑制和组织动态平衡中的作用，因为新出现的证据表明，DDR因子也参与了分化过程。我们打算阐明DDR激酶、ATM和其他DDR因子在干细胞存活和分化中的作用。此外，我们希望通过研究神经干细胞与其终末分化的后代中成糖细胞瘤相关癌基因的表达是否会导致衰老、细胞凋亡、转化或去分化，从而为癌症起源的研究做出贡献。