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

IFN-γ 对 EAE 神经干细胞修复潜力的影响

• 批准号: 7579112
• 负责人: Samia J. Khoury
• 金额: $ 43.16万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579112
• 关键词: AIDS Dementia Complex; Adult; Affect; Alzheimer' s Disease; Animal Model; Astrocytes; Autoimmune Process; Axon; CD80 gene; CXCL12 gene; Cell Transplants; Cells; Central Nervous System Degenerative Diseases; Chronic; Chronic Disease; Chronic Phase of Disease; Data; Demyelinating Diseases; Demyelinations; Disease; EGF gene; Encephalomyelitis; Environment; Exhibits; Experimental Autoimmune Encephalomyelitis; Experimental Models; Exposure to; Failure; Gene Expression; Gene Proteins; Genes; Immunologic Receptors; Immunotherapy; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Interferon Type II; Interferons; LIF gene; Label; Lesion; Mediating; Modeling; Molecular; Multiple Sclerosis; Mus; Myelin; Natural regeneration; Nerve Degeneration; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neurologic; Oligodendroglia; Pathogenesis; Pathway interactions; Patients; Phase; Population; Process; Proliferating; Property; Relapse; Research Personnel; Resistance; Role; STAT1 gene; Stem cells; Symptoms; System; Transplantation; Undifferentiated; base; cell motility; cytokine; disability; experience; in vivo; in vivo Model; migration; multipotent cell; nerve stem cell; neurogenesis; programs; public health relevance; relating to nervous system; repaired; response; self-renewal; stem cell differentiation; subventricular zone; transcription factor

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.

描述（由申请人提供）：成年哺乳动物中枢神经系统包含一群未成熟、未分化的多能细胞，即神经干细胞（NSCs），可能用于神经退行性和脱髓鞘疾病的修复。反过来，NSCs可以产生少突胶质细胞祖细胞（OPCs）和其他髓鞘细胞，以及神经和胶质前体。NSCs修复成人损伤的能力已经在几个实验系统中得到证实。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，髓鞘再生成和神经再生的程度不够。我们之前已经表明，NSCs表达许多免疫受体，如CD80和CD86，这些受体因暴露于IFN-？或TNF-a。我们现在有初步数据表明IFN-？影响了NSC内在的自我更新能力和迁移能力。我们在这个建议中的目标是：目标1。为了检验IFN-？以及转录因子STAT1对NSCs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NSCs对干扰素反应的关键因素。以及IFN- 1后自我更新能力的丧失？治疗依赖于STAT1。使用STAT1 KO小鼠，我们将在炎症环境中确定STAT1缺乏对体内NSCs的影响。然后我们将研究IFN-？对自我更新至关重要的基因和蛋白质。目标2。)为了检验IFN- ？NSCs在体内的迁移和体外的分子程序。我们的初步数据表明，NSCs向SDF1的迁移受到IFN-？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IFN-？关于迁移相关基因。目标3。)研究STAT1在体内对NSCs分化的影响，以及体外以神经源性分化为重点的分化分子程序的影响。我们的假设得到了初步数据的支持，即炎症介质与干细胞程序的主要调节因子相互作用并修改这些程序。上面概述的实验计划将允许我们开始揭示这些相互作用的复杂性。公共卫生相关性：IFN-？是一种炎症细胞因子，在多发性硬化症、阿尔茨海默病和HIV痴呆等许多疾病中，在中枢神经系统中被上调。了解IFN-？影响NSCs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。