Transcriptional Control of Adult Neural Stem Cells

描述(申请人提供)：神经干细胞存在于成人大脑中，并不断产生新的神经元，对多种生理和病理刺激做出反应，并可能参与学习和记忆、癫痫、抑郁和损伤后的脑部重塑。最新的数据还表明，神经干细胞和致命的脑瘤之间存在相互联系。这项应用的长期目标是了解成人神经干细胞的调节及其在正常或疾病条件下的作用。转录因子作为多种细胞外和细胞内信号通路的整合因子，通过与基因组的直接相互作用，在细胞类型的确定、增殖和分化中发挥着关键作用。我们的研究将使用其中一种转录因子作为分子工具。我们和其他人证明了孤儿核受体TLX(NR2E1)对于成体神经干细胞在神经源性壁龛中的维持和增殖是绝对必要的。我们进一步表明，TLX依赖的成人神经发生有助于空间学习和记忆。通过使用最先进的分子、细胞和小鼠遗传学方法，这里描述的研究试图了解：1)神经干细胞规范和维持的转录逻辑；以及2)TLX依赖的神经干细胞在脑相关疾病中的作用。这项工作的结果将为我们理解神经干细胞的生物学及其在疾病条件下的作用提供新的见解。这些知识将是实现以这些干细胞为治疗目标的承诺的关键。 公共卫生相关性：成人大脑中神经干细胞的存在为某些脑损伤、神经退行性变和抑郁症的再生治疗带来了巨大的希望。随之而来的是，这些细胞可能是致命性脑瘤的起因和延续。我们建议的研究将集中于了解成人神经干细胞在正常和疾病条件下的调节和功能。

DESCRIPTION (provided by applicant): Neural stem cells exist in the adult brain and continually generate new neurons, which respond to multiple physiological and pathological stimulations and are potentially involved in learning and memory, epilepsy, depression, and brain remodeling after injury. Most recent data also demonstrate an interconnection between neural stem cells and deadly brain tumors. The long-term goal of this application is to understand the regulation of adult neural stem cells and their roles under normal or diseased conditions. As integrators of multiple extracellular and intracellular signaling pathways and through direct interaction with the genome, transcription factors play key roles in cell type specification, proliferation, and differentiation. Our research will use one of these transcription factors as a molecular tool. We and others demonstrated that orphan nuclear receptor TLX (NR2E1) is absolutely required for the maintenance and proliferation of adult neural stem cells in neurogenic niches. We further showed that TLX-dependent adult neurogenesis contributes to spatial learning and memory. By employing the most advanced molecular, cellular and mouse genetic approaches, the studies described here seek to understand: 1) the transcriptional logic underlying the specification and maintenance of neural stem cells; and 2) the role of TLX-dependent neural stem cells in brain-related diseases. Results from this work will provide novel insights into our understanding of the biology of neural stem cells and their role under diseased conditions. Such knowledge will be pivotal to fulfill the promise of targeting these stem cells for therapeutics. PUBLIC HEALTH RELEVANCE: The existence of neural stem cells in the adult brain generates great hope for regenerative therapy for certain brain injuries, neurodegeneration, and depression. Concomitantly, these cells may be the cause and perpetuator of deadly brain tumors. Our proposed research will focus on understanding the regulation and function of adult neural stem cells under normal and disease conditions.