Impact of IFN-gamma on Neural Stem Cell Repair Potential in EAE

描述(申请人提供)：成年哺乳动物的中枢神经系统含有一群未成熟、未分化、多能的细胞，神经干细胞(NSCs)可用于神经退行性疾病和脱髓鞘疾病的修复。神经干细胞可以产生少突胶质前体细胞(OPC)和其他髓鞘细胞，以及神经和神经胶质前体细胞。在几个实验系统中，已经证明了神经干细胞修复成人损伤的能力。然而，在多发性硬化症及其动物模型实验性自身免疫性脑脊髓炎(EAE)中，重新髓鞘形成和神经再生没有发生到足够的程度。我们以前已经证明，神经干细胞表达许多免疫受体，如CD80和CD86，这些受体在暴露于干扰素？或肿瘤坏死因子-a。我们现在有初步数据表明，干扰素-？影响神经干细胞固有的自我更新能力和迁移能力。我们在这项建议中的目标是：目标1。)检测干扰素-？转录因子STAT1对神经干细胞体内自我更新程序和体外分子程序的影响。我们的初步数据表明，STAT1是神经干细胞对干扰素的应答的一个关键因素。干扰素后自我更新能力的丧失？治疗依赖于STAT1。利用STAT1 KO小鼠，我们将在炎症环境中确定STAT1缺陷对体内NSCs的影响。然后我们将研究干扰素-？的作用。对自我更新至关重要的基因和蛋白质。目标2。)检测干扰素-？关于神经干细胞在体内的迁移和体外分子程序。我们的初步数据表明，神经干细胞向SDF1的迁移受到干扰素-β的抑制。在体外，这是独立于STAT1的。我们将使用体内模型来研究炎症对干细胞迁移的影响，并将评估干扰素？关于迁移相关基因的研究。目标3。)目的：研究STAT1在体内对神经干细胞分化的影响，以及以神经源性分化为重点的体外分化分子程序。我们的假设得到了初步数据的支持，即炎症介质与干细胞计划的主要调节者相互作用，并修改这些计划。上面概述的实验计划将使我们能够开始解开这些相互作用的复杂性。与公共卫生相关：干扰素？是一种炎性细胞因子，在许多疾病中，如多发性硬化症、阿尔茨海默病和艾滋病毒痴呆症中，中枢神经系统上调。了解干扰素是如何产生的？影响神经干细胞的增殖和修复能力对于了解这些神经退行性疾病的发病机制和找到可以逆转神经系统损害的治疗方法至关重要。

DESCRIPTION (provided by applicant): The adult mammalian central nervous system contains a population of immature, undifferentiated, multipotent cells, neural stem cells (NSCs) that may be called upon for repair in neurodegenerative and demyelinating diseases. NSCs may, in turn, give rise to oligodendrocyte progenitor cells (OPCs) and other myelinating cells, as well as neural and glial precursors. The capacity of NSCs to repair damage in the adult has been demonstrated in several experimental systems. However, in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE), remyelination and neuro-regeneration do not occur to a sufficient extent. We have previously shown that NSCs express a number of immune receptors such as CD80 and CD86 that are upregulated by exposure to IFN-? or TNF-a. We have now preliminary data suggesting that IFN-? affects the intrinsic NSC properties of self-renewal capacity and migratory capacity. Our aims in this proposal are: Aim 1.) To examine the effect of IFN-? and the transcription factor STAT1 on the self-renewal program of NSCs in vivo and on their molecular program in vitro. Our preliminary data suggest that STAT1 is a critical factor for the responses of NSCs to interferon-? and that loss of self- renewal capacity after IFN-? treatment is STAT1 dependent. Using STAT1 KO mice, we will we will determine the effect of STAT1 deficiency on NSCs in vivo in an inflammatory environment. We will then investigate the effects of IFN-? on genes and proteins that are critical for self-renewal. Aim 2.) To examine the effect of IFN- ? on migration of NSCs in vivo and on the molecular program in vitro. Our preliminary data suggest that migration of NSCs to SDF1 is inhibited by IFN-? in vitro and that this is independent of STAT1. We will use in vivo models to investigate the effects of inflammation on migration of stem cells, and will evaluate the molecular impact of IFN-? on migration related genes. Aim 3.) To examine the effect of STAT1 on differentiation of NSCs in vivo and on the differentiation molecular program in vitro focusing on neurogenic differentiation. Our hypothesis, supported by preliminary data, is that inflammatory mediators interact with master regulators of stem cell programs and modify these programs. The experimental plan outlined above will allow us to begin unraveling the complexities of these interactions. Public health relevance: IFN-? is an inflammatory cytokine that is up-regulated in the central nervous system in many diseases such as MS, Alzheimer's disease and HIV dementia. Understanding how IFN-? impacts the ability of NSCs to proliferate and repair is critical in understanding the pathogenesis of these neurodegenerative diseases and finding treatments that can reverse damage to the nervous system.