Effects of Alcohol on Stem Cells in the Adult Brain

酒精对成人大脑干细胞的影响

• 批准号: 8259052
• 负责人: MICHAEL W MILLER
• 金额: --
• 依托单位: SYRACUSE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259052
• 关键词: Accounting; Activity Cycles; Adolescence; Adolescent; Adult; Affect; Age; Alcohol abuse; Alcohols; Attenuated; Behavior; Biochemical; Biological Models; Brain; Brain Diseases; Bromodeoxyuridine; Cell Count; Cell Cycle; Cell Death; Cell Proliferation; Cell Proliferation Regulation; Cell Survival; Cell Transplants; Cells; Cerebral cortex; Cessation of life; Chronic; Complement; Data; Defect; Dementia; Development; Disease; Environment; Environmental Risk Factor; Epigenetic Process; Ethanol; Ethanol toxicity; Functional disorder; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Growth; Growth Factor; Healthcare; Heterotopic Transplantation; Hippocampal Formation; Hippocampus (Brain); Immunohistochemistry; In Situ; In Vitro; Label; Laboratories; Learning; Memory; Memory Loss; Mental disorders; Methods; Methylation; Mitotic; Molecular Biology; Neuroglia; Neurons; Phase; Play; Population; Process; Production; Proliferating; Prosencephalon; Proteins; Receptor Activation; Regulation; Replication-Associated Process; Research Design; Series; Shapes; Site; Staging; Stem cells; Substance abuse problem; System; Testing; Time; Transforming Growth Factor beta; Transforming Growth Factors; Transplantation; Veterans; Wernicke-Korsakoff Syndrome; abstracting; age related; alcohol effect; alcohol response; base; cell growth; defined contribution; dentate gyrus; genetic profiling; human TFRC protein; in vivo; interdisciplinary approach; nerve stem cell; neurotrophic factor; novel; postnatal; precursor cell; receptor; research study; response; stem cell niche

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.

描述（由申请人提供）： 项目摘要/摘要。操纵干细胞为许多脑部疾病提供了最有希望的治疗方法之一。这些疾病之一可能是酒精和药物滥用。慢性酗酒是退伍军人中最大的医疗保健问题之一。特别是，酗酒会导致学习和记忆丧失以及脑功能障碍，例如痴呆和科尔萨科夫综合症，并且它是包括精神障碍和肝脑病在内的许多疾病的共病因素。学习和记忆的主要贡献者是神经干细胞（NSC）的产生及其后代的命运（例如神经元或神经胶质细胞）。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 的环境决定了其增殖活动和能力。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循环群体的关键功能。有趣的是，NSC 的产生和 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决定，并且在发育中的大脑中，它似乎通过 TGF1 发挥作用。本研究将检验乙醇通过影响 TGF1 改变神经原发生的假设。 $ 拟议项目由一系列三项互补研究组成，旨在研究乙醇影响 NSC 活动的机制。 (1) 学习和记忆取决于海马结构齿状回新神经元的产生。我们将使用器官型培养物来确定乙醇（a）对齿状回中 NSC 增殖的影响，（b）对这些 NSC 存活的影响，以及（c）对这些 NSC 表达的 TGF1 系统激活的影响。 (2) 源自前脑 NSC 的 NSC 系将用于探索乙醇对 TGF1 调节的细胞增殖和命运决定的影响。此外，我们将鉴定乙醇和/或 TGF1 上调和下调以及沉默（甲基化）的基因。 (3) 将移植 NSC，以确定乙醇和/或 TGF1 对遗传和环境贡献的影响，从而确定循环行为和定义细胞命运。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 3 将通过检查青少年和成人来检查年龄依赖性变化，以便进一步确定 TGF1 是否是乙醇的目标。 作为一个整体，拟议的研究将评估酒精引起的痴呆症的机制。此外，它们还将提供（a）改善酒精引起的缺陷的基础和（b）有关正常大脑中神经营养蛋白系统组织的有价值的新数据。 公共卫生相关性： 项目叙述了解酗酒的后果是退伍军人管理局指定的研究领域，这是有充分理由的。影响退伍军人的一些最具破坏性的疾病是由酗酒引起的长期缺陷。这些疾病不仅对个人造成毁灭性影响，而且给医院和家庭护理系统带来负担。值得赞扬的是，退伍军人管理局是此类研究领域公认的领导者。退伍军人管理局的研究人员极大地增进了我们对酒精引起的缺陷的理解。尽管我们在 VAMC 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。拟议的工作是对乙醇引起的变性的病因学进行系统分析。重要的是，我们开始探索酒精毒性的机制，以便制定开发酒精滥用治疗方法的策略。酗酒是一个紧迫的问题，不仅因为其遗传影响，还因为患有创伤后应激障碍 (PTSD) 的退伍军人经常酗酒。拟议的研究将生成有关正常中枢神经系统中 NSC 生成以及乙醇影响的数据。这些数据对于我们了解其他神经退行性疾病（例如阿尔茨海默病和帕金森病）以及制定解决这些疾病的治疗策略至关重要。