Neural Stem Cell Dysfunction in Delayed Radiation Injury

描述（申请人提供）：颅放射治疗的一个常见的和使人衰弱的副作用是认知能力的永久性和持续进行性下降，包括学习和记忆受损，尽管以前的工作已经涉及海马功能的改变，但我们首次表明颅放射损伤成人神经干细胞，消除海马神经发生并永久破坏海马微环境，使其不能支持神经发生，即使在用未辐照的干细胞重建后，辐射海马亚颗粒区显示两个重要的长期改变，可能是其无法支持神经发生：正常神经干细胞活性的丧失和“神经血管生成”微环境的破坏。 拟议的实验进一步表征成人神经干细胞的辐射敏感性，并探讨辐射防护以及重建策略的潜在效用，以减少辐射对成人大脑神经发生的影响。

DESCRIPTION (provided by applicant): A common and debilitating side effect of cranial radiation therapy is a permanent and continually progressive decline in cognition that includes impaired learning and memory, Although previous work has implicated altered hippocampal function in this deficit, we show for the first time that cranial radiation injures adult neural stem cells, ablates hippocampal neurogenesis and permanently disrupts the hippocampal microenvironment making it unable to support neurogenesis, even following reconstitution with non-irradiated stem cells, The irradiated hippocampal subgranule zone displays two important long-term alterations that may account for its inability to support neurogenesis: a loss of normal neural stem cell activity and disruption of the "neuro-angiogenic" microenvironment. The proposed experiments further characterize the radiation sensitivity of adult neural stem cells and explore the potential utility of radio-protective as well as reconstitution strategies to reduce the impact of radiation on neurogenesis in the adult brain.