Role of Opiates in Alcohol-Induced Neurotoxicity- Diversity supplement

阿片类药物在酒精引起的神经毒性中的作用 - 多样性补充剂

• 批准号: 9094169
• 负责人: DIPAK KUMAR SARKAR
• 金额: $ 3.06万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9094169
• 关键词: Adult; Alcohol-Induced Neurotoxicity; Alcohols; Antioxidants; Apoptotic; Award; Biological Assay; Brain-Derived Neurotrophic Factor; Cell physiology; Cessation of life; Communication; Cyclic AMP; Data; Defect; Development; Endorphins; Ethanol; Funding; Generations; Genes; Grant; Hypothalamic structure; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Instruction; Life; Mediating; Methods; Microglia; Modeling; NADP; Neonatal; Neurons; Newborn Infant; Nuclear; Opiates; Opioid Receptor; Oxidants; Oxidases; Oxidative Stress; Pathway interactions; Peptides; Physiological; Population; Primary Cell Cultures; Pro-Opiomelanocortin; Process; Production; Proteomics; Rattus; Reactive Oxygen Species; Regulation; Research; Risk; Role; Series; Signal Transduction; Stress; TNF gene; Techniques; Testing; Transforming Growth Factors; Western Blotting; Work; alcohol exposure; biological adaptation to stress; chemokine; cytokine; early life exposure; feeding; hypothalamic-pituitary-adrenal axis; immune function; immunocytochemistry; in vivo; knock-down; nerve stem cell; neurotoxic; neurotoxicity; neurotrophic factor; novel; oxidative damage; pituitary adenylate cyclase activating polypeptide; prevent; programs; receptor function

Research pertaining to this grant has evolved toward determining the role of microglia in mediating ethanol apoptotic action on developing R-endorphin neurons involved in regulation ofthe hypothalamic pituitary adrenal axis (HPA) functions. The work conducted by us during the past funding period of the MERIT award demonstrated that alcohol exposure during early life causes activation of microglial cells and releases cytokines and chemokines that impact the physiological functions of hypothalamic neurons. Furthermore, early life exposure of ethanol may program the microglial cell population to produce more inflammatory cytokines following a stress challenge in the adulthood. Also, B-endorphin neurons that regulate the HPA axis are not only a target of inflammatory cytokines and chemokines but also a modulator of microglial cell functions. Given the lack of information how microglia and BEP interact to control stress responses and the availability of methods of culturing pure B-endorphin neurons from rat neuronal stem cells, we propose to test the following hypotheses: i) alcohol exposures stimulate microglia to produce inflammatory cytokines including TNF-a that activates the nuclear factor-KB (NFKB) pathway and NADPH oxidase to induce apoptotic signaling in developing B-endorphin neurons; ii) li-endorphin neurons influences the ethanol's ability to increase inflammatory cytokines production by altering opioid receptor functions in microglial cells; and iii) early-life alcohol exposures program the microglial cell population to produce more inflammatory cytokines following a stress challenge during the adulthood. We will employ various state-of-the art techniques involving in vitro differentiated pure B-endorphin cells, primary cultures of microglial cells, neonatal model of alcohol feeding, microarray and proteomic approaches, western blot, realtime PCR, MeDIP assay, double immunocytochemistry, gene knocking-down. We will also use both in vitro and in vivo approaches. We anticipate these studies will identify whther a bi-directional communication between microglia and B-endorphin within the hypothalamus may predict risk for stress abnormality in a model of developmental alcohol exposures. RELEVANCE (See instructions): The proposed series of studies should continue to generate valuable data for better understanding pf ethanol's neurotoxic action on developing B-endorphin neurons. Additionally, the proposed research should identify compounds acting on novel targets to inhibit the release of a wide range of proinflammatory factprs from overactivated microglia that might be critical for preventing of B-endorphin neuronal death.

与这笔资助相关的研究已经发展到确定小胶质细胞在介导乙醇中的作用 对参与下丘脑垂体调节的发育中的 R-内啡肽神经元的凋亡作用 肾上腺轴（HPA）功能。我们在过去的 MERIT 奖资助期间所开展的工作 证明生命早期接触酒精会导致小胶质细胞激活并释放 影响下丘脑神经元生理功能的细胞因子和趋化因子。此外， 生命早期接触乙醇可能会使小胶质细胞群产生更多炎症 成年期压力挑战后的细胞因子。此外，调节 HPA 的 B-内啡肽神经元 轴不仅是炎症细胞因子和趋化因子的靶标，也是小胶质细胞的调节剂 功能。鉴于缺乏小胶质细胞和 BEP 如何相互作用来控制应激反应和 从大鼠神经元干细胞中培养纯 B-内啡肽神经元的方法的可用性，我们建议 测试以下假设：i) 酒精暴露刺激小胶质细胞产生炎症细胞因子 包括激活核因子-KB (NFKB) 途径的 TNF-a 和 NADPH 氧化酶以诱导 发育中的 B-内啡肽神经元中的细胞凋亡信号传导； ii) li-内啡肽神经元影响乙醇的 通过改变小胶质细胞中的阿片受体功能来增加炎症细胞因子的产生； iii) 生命早期的酒精暴露会使小胶质细胞群产生更多的炎症 成年期应激挑战后的细胞因子。我们将采用各种最先进的技术 涉及体外分化的纯 B-内啡肽细胞、小胶质细胞原代培养物的技术， 酒精喂养新生儿模型、微阵列和蛋白质组学方法、蛋白质印迹、实时 PCR、 MeDIP 测定、双重免疫细胞化学、基因敲低。我们还将使用体外和体内 接近。我们预计这些研究将确定之间是否存在双向通信 下丘脑内的小胶质细胞和 B-内啡肽可以预测模型中应激异常的风险 发育性酒精暴露。 相关性（参见说明）： 拟议的系列研究应继续产生有价值的数据，以更好地理解 pf 乙醇对发育中的 B-内啡肽神经元具有神经毒性作用。此外，拟议的研究应该 鉴定作用于新靶点的化合物，以抑制多种促炎因子的释放 来自过度激活的小胶质细胞，这可能对于预防 B-内啡肽神经元死亡至关重要。