Inflammatory Modulation of Neural Stem Cell Function

描述（由申请人提供）：影响成人海马功能的生理变化伴随着神经发生的平行改变，人们认为学习和记忆可能依赖于持续的神经发生。用于治疗癌症的颅放射治疗是导致神经发生受损和海马功能逐渐严重缺陷的最显著的损伤例子之一。在对啮齿动物的这一过程进行建模时，我们观察到慢性炎症伴随着辐射损伤，这表明炎症过程可能导致神经干细胞功能障碍。随后的研究表明，神经炎症本身是一种有效的神经发生抑制剂，用吲哚美辛（一种常见的非甾体抗炎药）进行炎症阻断，可以恢复内毒素诱导炎症后的神经发生，并增强颅脑照射后的神经发生。此外，趋化因子MCP-1缺失的动物对辐射的长期影响有抵抗力，并且在照射后1个月神经发生恢复到正常水平。尽管炎症阻断逆转了对神经发生的抑制，但尚不清楚炎症如何影响神经发生，或者干细胞活性的这些扰动是否影响学习和记忆功能。这一应用表明，炎症的促炎阶段通过以下途径影响海马中的神经干细胞：1)炎症细胞、细胞因子和趋化因子对干细胞及其后代的直接作用；2)炎症细胞、细胞因子对干细胞微环境的间接作用；3)下丘脑-垂体-肾上腺轴的炎症调节以及随后糖皮质激素的升高。使用原代神经干细胞培养以及基因或手术缺乏关键炎症介质的动物，将使我们能够测试这些关于神经干细胞活性、成年海马神经发生和海马学习和记忆功能的假设。

DESCRIPTION (provided by applicant): Physiological changes that affect hippocampal function in the adult are accompanied by parallel alterations in neurogenesis and it is thought that learning and memory may depend on continued neurogenesis. Cranial radiation therapy for the treatment of cancer is 1 of the most striking examples of injury that causes impaired neurogenesis and progressively severe deficits in hippocampal function. In modeling this process in rodents, we observed that chronic inflammation accompanies radiation injury, suggesting that inflammatory processes may contribute to neural stem cell dysfunction. Subsequent work has shown that neuroinflammation alone is a potent inhibitor of neurogenesis and that inflammatory blockade with indomethacin, a common non-steroidal anti-inflammatory drug, restores neurogenesis following endotoxin-induced inflammation and augments neurogenesis following cranial irradiation. In addition, animals with deficits in the chemokine MCP-1 are resistant to the long-term effects of radiation and neurogenesis returns to normal levels 1 month after irradiation. Although inflammatory blockade reverses the inhibition of neurogenesis, it is not known how inflammation influences neurogenesis or whether these perturbations in stem cell activity influence learning and memory function. This application proposes that the pro-inflammatory phase of inflammation influences neural stem cells in the hippocampus by 1) the direct action of inflammatory cells, cytokines and chemokines on stem cells and their progeny, 2) by the indirect effects of inflammatory cells, cytokines on the stem cell microenvironment and 3) by the inflammatory modulation of the hypothalamic-pituitary-adrenal axis and subsequent elevation of glucocorticoids. The use of primary neural stem cell cultures as well as animals that are genetically or surgically deficient in key inflammatory mediators will allow us to test these hypotheses with regards to neural stem cell activity, adult hippocampal neurogenesis, and hippocampal learning and memory function.