Effects of Alcohol on Stem Cells in the Adult Brain

描述(由申请人提供)： 项目摘要/摘要。操纵干细胞为许多大脑疾病提供了最有希望的治疗方法之一。潜在的，这些障碍之一是酗酒和滥用药物。长期酗酒是退伍军人最大的医疗保健问题之一。特别是，酒精滥用可导致学习和记忆丧失以及大脑功能障碍，如痴呆症和科萨科夫综合症，它是许多疾病的共病因素，包括精神障碍和肝性脑病。学习和记忆的主要贡献者是神经干细胞(NSCs)的产生及其后代的命运(例如神经元或胶质细胞)。在青少年和成人中，这种产生主要局限于大脑皮层，特别是齿状回。NSC的环境决定了它的增殖能力和能力。构成NSC生态位的一类蛋白质是生长因子。其中一种独特的蛋白质是转化生长因子(TGF)1；它发挥着将细胞移出周期种群的关键功能。有趣的是，NSC的产量和TGF1的表达随着年龄的增长而下降。乙醇可以影响细胞增殖和细胞命运的决定，在发育中的大脑中，它似乎通过TGF1起作用。本研究将验证乙醇通过对TGF1的影响而改变神经元发生的假说。$拟议的项目由三项互补性研究组成，旨在研究乙醇影响神经干细胞活性的机制。(1)学习和记忆依赖于海马齿状回新神经元的产生。我们将使用器官类型培养来确定乙醇对齿状回神经干细胞增殖的影响，(B)对这些神经干细胞的存活的影响，以及(C)对这些神经干细胞表达的TGF1系统的激活的影响。(2)从前脑神经干细胞来源的$NSCs株将被用来探索乙醇对TGF1调控的细胞增殖和命运决定的影响。此外，我们将识别上调和下调并被乙醇和/或TGF1沉默(甲基化)的基因。(3)神经干细胞将被移植，以确定$乙醇和/或TGF1对决定循环行为和$定义细胞命运的遗传和环境贡献的影响。这些研究将使用多学科方法(分子生物学、解剖学和生化方法)来检查互补的模型系统。目标1和目标3将通过检查青少年和成年人来检查年龄相关性变化，以进一步确定TGF1是否为酒精的靶标。作为一个单元，拟议的研究将评估酒精导致痴呆的机制。此外，它们将提供(A)改善酒精引起的缺陷的基础和(B)关于正常大脑中神经营养素系统组织的有价值的新数据。 公共卫生相关性： 了解酗酒后果的项目叙事是退伍军人管理局指定的研究领域，而且有很好的理由。影响退伍军人的一些最具破坏性的疾病是酗酒造成的长期缺陷。这些疾病是毁灭性的，不仅因为它们对个人的影响，而且因为它们给医院和家庭护理系统带来了负担。值得称赞的是，退伍军人管理局在这类研究中是公认的领导者。退伍军人管理局的研究人员极大地提高了我们对酒精引起的缺陷的理解。尽管我们在VAMCS的酒精研究方面取得了进展，但乙醇毒性的机制仍然难以捉摸。这项拟议的工作是对乙醇诱导的变性的病因进行系统的分析。重要的是，我们必须开始探索酒精毒性的机制，以便能够制定治疗酒精滥用的策略。酒精中毒是一个紧迫的问题，不仅是因为它的遗传影响，还因为酒精滥用往往发生在患有创伤后应激障碍的退伍军人身上。这项拟议的研究将产生关于正常中枢神经干细胞产生的数据以及乙醇的影响。这些数据对于我们了解其他神经退行性疾病(例如阿尔茨海默氏症和帕金森氏病)以及制定针对这些疾病的治疗策略至关重要。

DESCRIPTION (provided by applicant): Project Summary/Abstract. Manipulating stem cells offers one of the most promising treatments for a number of brain disorders. Potentially, one of these disorders is alcohol and substance abuse. Chronic alcohol abuse is one of the greatest health care problems among veterans. In particular, alcohol abuse can cause learning and memory loss and brain dysfunction, e.g., dementia and Korsakoff's Syndrome, and it is a co-morbid factor in many diseases including mental disorders and hepatoencephalopathy. A major contributor to learning and memory is the production of neural stem cells (NSCs) and their fate (e.g., neuron or glia) of their progeny. In the adolescent and adult, this production is largely restricted to cerebral cortex, and particularly, the dentate gyrus. The environment of a NSC defines its proliferative activity and capability. One class of proteins that comprises the NSC niche is growth factors. One such unique protein is transforming growth factor (TGF) 1; it plays the $ critical function of moving cells out of the cycling population. Interestingly, NSC production and TGF1expression decline with age. Ethanol can affect cell proliferation and cell fate decisions, and in the $ developing brain, it appears to act through TGF1. The present study will test the hypothesis that ethanol alters $ neuronogenesis through its effects on TGF1. $ The proposed project constitutes a series of three complementary studies designed to examine mechanisms through which ethanol can affect NSC activity. (1) Learning and memory depend upon the production of new neurons in the dentate gyrus of the hippocampal formation. We will use organotypic cultures to determine the effects of ethanol (a) on the proliferation of NSCs in the dentate gyrus, (b) on the survival of these NSCs, and (c) on the activation of TGF1 systems expressed by these NSCs. (2) Lines of $ NSCs derived from forebrain NSCs will be used to explore the effects of ethanol on TGF1-regulated cell $ proliferation and fate decisions. In addition, we will identify genes that are up- and down-regulated and are silenced (methylated) by ethanol and/or TGF1. (3) NSCs will be transplanted to determine the effects of $ ethanol and/or TGF1 on genetic and environmental contributions to determining cycling behavior and to $ defining cell fate. These studies will use a multidisciplinary approach (molecular biology, anatomical, and biochemical methods) to examine complementary model systems. Aims 1 and 3 will examine age-dependent changes by examining adolescents and adults in order to determine further if TGF1 is a target of ethanol. $ As a unit, the proposed studies will assess mechanisms that underlie alcohol-induced dementia. Furthermore, they will provide (a) the basis for ameliorating alcohol-induced defects and (b) valuable new data on the organization of neurotrophin systems in the normal brain. PUBLIC HEALTH RELEVANCE: Project Narrative Understanding the consequences of alcohol abuse is a VA Designated Research Area, and for good reason. Some of the most devastating disorders affecting veterans are long-term deficits caused by alcohol abuse. These disorders are devastating not only for their impact on the individuals, but also for the burden they place on the hospital and home care systems. To its credit, the VA is an acknowledged leader in such research. Our understanding of alcohol-induced deficits has been greatly advanced by VA researchers. Despite our progress in alcohol research at VAMCs, mechanisms of ethanol toxicity remain elusive. The proposed work is a systematic analysis of the etiology of ethanol-induced degeneration. It is important that we begin to explore mechanisms of alcohol toxicity so that strategies for developing treatments for alcohol abuse can be generated. Alcoholism is a pressing issue not only for its genetic implications, but also because alcohol abuse often develops in veterans suffering from PTSD. The proposed studies will generate data on NSC generation in the normal CNS and the effects of ethanol. Such data are of key importance for our understanding of other neurodegenerative diseases (e.g., Alzheimer's and Parkinson's Diseases) and for the developmental of therapeutic strategies to address these diseases.