Neural Stem Cell Dysfunction in Delayed Radiation Injury

描述(申请人提供)：颅脑放射治疗的一个常见的和衰弱的副作用是认知的永久性和持续的进行性下降，包括学习和记忆受损，尽管以前的工作已经在这种缺陷中涉及到海马体功能的改变，但我们首次证明颅骨辐射损伤成人神经干细胞，消融海马神经发生，并永久性地扰乱海马区微环境，使其无法支持神经发生，即使在与非辐射干细胞重建后，受照射的海马区颗粒区显示两个重要的长期变化，可能导致其无法支持神经发生：正常的神经干细胞活动丧失和破坏“神经新生血管”微环境。 拟议的实验进一步表征了成人神经干细胞的辐射敏感性，并探索了辐射防护和重建策略的潜在用途，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.