Inflammatory Modulation of Neural Stem Cell Function

描述(申请人提供)：影响成人海马体功能的生理变化伴随着神经发生的平行变化，人们认为学习和记忆可能依赖于持续的神经发生。头颅放射治疗癌症是最引人注目的损伤之一，它会导致神经发生受损和逐渐严重的海马体功能缺陷。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。随后的工作表明，神经炎症本身就是一种有效的神经发生抑制剂，而消炎药吲哚美辛是一种常见的非类固醇抗炎药，它可以恢复内毒素诱导的炎症后的神经再生，并增强颅脑照射后的神经再生。此外，缺乏趋化因子MCP-1的动物对辐射的长期影响具有抵抗力，神经发生在辐射后1个月恢复到正常水平。虽然炎症阻断逆转了对神经发生的抑制，但目前尚不清楚炎症是如何影响神经发生的，也不知道干细胞活动的这些干扰是否会影响学习和记忆功能。这一应用提出，炎症的促炎阶段通过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)通过炎症细胞和细胞因子对干细胞微环境的间接影响，以及3)通过对下丘脑-垂体-肾上腺轴的炎症调节和随后糖皮质激素的升高来影响海马区的神经干细胞。使用原代神经干细胞培养物以及因遗传或手术原因缺乏关键炎症介质的动物，将使我们能够测试关于神经干细胞活性、成年海马神经发生以及海马体学习和记忆功能的这些假说。

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.