Neurogenesis, Inflammation and Irradiation Injury

描述(申请人提供)：颅脑放射治疗导致学习、短期记忆和空间信息处理的海马区依赖功能的进行性缺陷。海马神经发生发生在整个成年期，被认为对正常的海马体功能很重要，在治疗性剂量的辐射后被消融。我们的初步工作表明，辐射通过破坏支持神经发生的微环境来抑制神经发生，这种破坏与慢性小胶质细胞炎症反应有关，抗炎治疗部分恢复了辐射后的神经发生。这项建议旨在进一步探讨炎症和神经发生之间的关系。具体地说，我们试图证明炎症是抑制神经发生的必要条件和充分条件，激活的小胶质细胞直接介导炎症对神经发生的影响，而促炎细胞因子白介素6(IL-6)在这一疾病过程中发挥重要作用。我们从拟议的研究中收集的信息将为神经发生所需的微环境条件提供有价值的见解，并可能突出颅脑放射治疗的认知副作用的治疗方法。

DESCRIPTION (provided by applicant): Cranial radiation therapy causes progressive deficits in the hippocampal-dependent functions of learning, short-term memory and spatial information processing. Hippocampal neurogenesis, which occurs throughout adulthood and is believed to be important to normal hippocampal function, is ablated following therapeutic doses of radiation. Our preliminary work demonstrates that irradiation inhibits neurogenesis by disrupting the microenvironment that supports neurogenesis, this disruption is associated with a chronic microglial inflammatory response, that anti-inflammatory therapy partially restores neurogenesis following irradiation. This proposal seeks to explore further the relationship between inflammation and neurogenesis. Specifically, we seek to demonstrate that inflammation is necessary and sufficient to inhibit neurogenesis, activated microglia directly mediate the effects of inflammation on neurogenesis, and the proinflammatory cytokine interleukin-6 (IL-6) plays a significant role in this disease process. The information we glean from the proposed studies will provide valuable insights into the microenvironmental conditions required for neurogenesis and may highlight therapeutic approaches for the cognitive side effects of cranial radiation therapy.