成体神经干细胞静息和激活的REST和miRNA17-92负反馈调控

Aging and its associated major diseases including cancers and neurodegenerative conditions pose a daunting challenge and burden to our health, social and economical systems. Advances in stem cell research can not only help our exploration of tissue homeostasis, aging and pathogenesis, but also open up new avenues and bases for disease therapy and regenerative medicine. The control of stem cell quiescence and activation is an urgent question of major scientific and clinical significance. However, due to the technical limitation and the scarity of adult stem cells, our mechanistic understanding of adult stem cell quiescence and activation remains limited. REST is a master transcription repressor and epigenetic factor. It can modulate the expression of thousands of genes and is crucial in physiological and pathological processes. We have recently made a conditional REST knockout mouse allelle and uncovered a key role for REST in epigenetic control of adult neural stem cell fates and the progression of neurogenesis. To expand our recent work, we have established and optimized robust yet simple quiescent neural stem cell culture systems. Our systems can recapture the quiescence、activation、self-renewal、 proliferation and differentiation of adult neural stem cells in vivo. They are scalable and can provide unlimited materials for genomic profiling and high throughput screening. Our pilot genomic profilings and bioinformatic analyses suggest that REST associated miRNAs and their targets can form molecular networks underlying the homeostatic propertity of adult neural stem cells. Among the network are REST and miRNA17-92 cluster. Our preliminary results suggest they mutually target each other and thereby constitute a negative feed-back loop. This feed-back loop represents a major regulatory pathway modulating adult neural stem cell quiescence and activation to achieve and sustain a homeostatic state. Utilizing interdiscipline approaches,techniques and systems, we hope to dissect in details this feedback loop and its role in adult neural stem cell fates. The proposed study can provide the bases for future exploration of the broad networks underlying adult neural stem cell fate choice and diseases.It has the very potential to provide novel insights and therapeautic targets for disease diagonistic and therapy.

衰老及其伴随的恶性肿瘤和神经退行性疾病为家庭、社会和国民经济带来了巨大压力。干细胞命运决定或分化调控异常可能会导致肿瘤或退行性疾病。干细胞的静息和激活机制是成体干细胞的命运决定或分化调控中非常关键的部分。研究干胞静息激活的机制可以为解析组织稳态、衰老、肿瘤发生机制提供新的思路和基础。但受技术手段和材料来源限制，我们对干细胞的静息激活知之甚少。我们希望在前期关于转录因子REST和神经再生的工作基础上， 利用体外静息神经干细胞诱导培养和分化体系，结合体内遗传学分析技术，解析REST和miRNA-17-92互为靶基因的负反馈网络通路，并研究其在调控成体神经干细胞静息激活增殖动态平衡中的作用。最终我们希望系统解析以REST为中心，miRNA和正负反馈为基础的分子网络，阐明它们如何控制神经干细胞静息和激活动态和成体再生，为成体干细胞在衰老及相关疾病中的应用提供坚实的理论基础和诊断治疗依据。

在本项目的主要目标是研究以REST和miRNA17-92负反馈调控通路为主的转录因子和miRNA网络系统对于神经干细胞静息激活平衡的调控作用与机理。在项目开题第一年我们取得了重要进展： 1）进一步明晰了REST和miRNA17-92的调控关系及其在神经干细胞静息激活中的功能； 2）发现REST和miRNA17-92相关的网络系统介导了细胞外因素对于干细胞静息激活的调控；利用体外细胞培养系统，我们已经研究分析了相关转录因子和小RNA在静息激活过程中的表达动态和功能，提示了它们在相关过程的重要作用；3）分析提示了这些相关的转录因子和小RNA同REST和miRNA17-92形成了一个交互调控的网络，共同介导细胞外因素对于干细胞静息激活的调控，我们下一步将对此进行细致的功能验证和机制分析；4）研究了潜在地可能建立神经干细胞静息激活调控的核心通路与机制，并对脑胶质瘤的研究有一定的启示意义。但是在我们的工作过程中，Cell Report 发表了miRNA17-92对于神经发育和增殖调控的研究，严重影响了我们工作的原创性。所以，我们决定进一步探讨该网络调控干细胞静息激活的下游机制。进一步研究表明，MYC，一个肿瘤细胞增殖和代谢中起至关重要的癌基因，转录因子，可能在神经干细胞的静息激活中发挥着关键的调节作用，因此，过去一年中我们详细分析了MYC在神经再生中的动态调节以及MYC如何通过对于细胞周期和细胞代谢的调节，来调控神经干细胞的静息与激活。同时，我们建立了人和猴子的神经干细胞静息增殖培养系统（已发表文章两篇），并开展了大量的组学水平的研究，相关的工作正在进展中，预期将会给相关领域带来突破性的进展。基于本项目研究，我们已经发表4篇文章，还有1篇在修。另外两个研究进展中，一个拟投stem cell report, 一个拟投Cell Stem Cell。

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