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

描述（由申请人提供）：成年哺乳动物中枢神经系统含有一群未成熟、未分化、多能细胞，即神经干细胞（NSC），可用于神经退行性和脱髓鞘疾病的修复。神经干细胞又可以产生少突胶质细胞祖细胞（OPC）和其他髓鞘形成细胞，以及神经和神经胶质前体。神经干细胞修复成人损伤的能力已在几个实验系统中得到证实。然而，在多发性硬化症及其实验性自身免疫性脑脊髓炎（EAE）动物模型中，髓鞘再生和神经再生没有充分发生。我们以前已经表明，神经干细胞表达了一些免疫受体，如CD 80和CD 86的上调暴露于IFN-？或TNF-α。我们现在有初步的数据表明，IFN-？影响神经干细胞的自我更新能力和迁移能力。我们在本建议中的目标是：目标1。为了检测IFN-？以及转录因子STAT 1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，STAT 1是神经干细胞干扰素-？以及IFN-γ后自我更新能力的丧失？治疗依赖于STAT 1。使用STAT 1 KO小鼠，我们将确定在炎症环境中STAT 1缺陷对体内NSC的影响。然后，我们将研究干扰素-？对自我更新至关重要的基因和蛋白质。目标2）为了检测IFN-？对神经干细胞在体内迁移和体外分子程序的影响。我们的初步数据表明，迁移的神经干细胞SDF 1抑制IFN-？在体外，这是独立的STAT 1。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IFN-γ的分子影响。与迁移相关的基因。目标3）研究STAT 1对神经干细胞体内分化的影响，以及对体外神经源性分化分子程序的影响。我们的假设，初步数据的支持，是炎症介质与主调节干细胞程序和修改这些程序。上面概述的实验计划将使我们开始解开这些相互作用的复杂性。公共卫生相关性：IFN-？是一种炎性细胞因子，在许多疾病如MS、阿尔茨海默病和HIV痴呆症的中枢神经系统中上调。了解IFN-？影响神经干细胞增殖和修复的能力对于理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伤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.