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: 7931185
• 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/7931185
• 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。操纵干细胞为多种脑部疾病提供了最有希望的治疗方法之一。可能，其中一种是酒精和滥用药物。慢性酒精滥用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力丧失以及脑功能障碍，例如痴呆症和科萨科夫综合症，这是许多疾病的合并因素，包括精神障碍和肝癌。学习和记忆的主要因素是神经干细胞（NSC）及其后代的命运（例如神经元或神经胶质）的产生。在青春期和成年人中，这种产量在很大程度上仅限于脑皮质，尤其是齿状回。 NSC的环境定义了其增殖活性和能力。一类包含NSC利基市场的蛋白质是生长因子。一种独特的蛋白质是转化生长因子（TGF）1。它扮演着将细胞从骑自行车人群中移出的关键功能。有趣的是，随着年龄的增长，NSC生产和TGF1表达下降。乙醇会影响细胞增殖和细胞命运决策，在$发育的大脑中，它似乎通过TGF1起作用。本研究将检验以下假设：乙醇通过其对TGF1的影响改变$神经发生。 $拟议的项目构成了一系列互补研究，旨在检查乙醇可以影响NSC活动的机制。 （1）学习和记忆取决于海马形成的齿状回中新神经元的产生。我们将使用器官型培养物来确定乙醇（a）对齿状回的NSC的增殖的影响，（b）对这些NSC的存活，以及（c）对这些NSC表达的TGF1系统的激活。 （2）源自前脑NSC的$ NSC线将用于探索乙醇对TGF1调节的细胞$增殖和命运决策的影响。此外，我们将确定乙醇和/或TGF1的上调和下调并沉默（甲基化）的基因。 （3）将对NSC进行移植，以确定$乙醇和/或TGF1对确定循环行为以及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）来检查互补模型系统。目标1和3将通过检查青少年和成年人来检查年龄依赖性变化，以进一步确定TGF1是否是乙醇的靶标。 $作为一个单位，拟议的研究将评估酒精诱导痴呆症基础的机制。此外，它们将提供（a）改善酒精引起的缺陷的基础，以及（b）关于正常大脑中神经营养系统组织的宝贵新数据。 公共卫生相关性： 理解酒精滥用的后果的项目叙事是一个有充分理由的VA指定研究领域。影响退伍军人的一些最具破坏性的疾病是由于酗酒而造成的长期缺陷。这些疾病不仅造成了对个人的影响，而且还因为它们在医院和家庭护理系统上的负担而造成了灾难性的影响。值得称赞的是，VA是此类研究的公认领导者。 VA研究人员大大提出了我们对酒精引起的赤字的理解。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。提出的工作是对乙醇诱导变性的病因的系统分析。重要的是，我们必须开始探索酒精毒性的机制，以便可以制定用于开发酗酒治疗的策略。酒精中毒不仅是其遗传意义的紧迫问题，而且还因为酗酒经常在患有PTSD的退伍军人中发展。拟议的研究将生成有关正常中枢神经系统中NSC生成的数据和乙醇的作用。此类数据对于我们对其他神经退行性疾病的理解至关重要（例如，阿尔茨海默氏症和帕金森氏病）以及解决这些疾病的治疗策略的发展。