EFFECTS OF ETHANOL EXPOSURE ON HYALURONAN-MEDIATED ADULT NEUROGENESIS

乙醇暴露对透明质酸介导的成人神经发生的影响

• 批准号: 8357865
• 负责人: Larry S. Sherman
• 金额: $ 3.63万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357865
• 关键词: Adult; Alcohol consumption; Alcoholism; Alcohols; CD44 gene; Cell Proliferation; Cell Survival; Data; Enzymes; Ethanol; Funding; Genes; Genetic Transcription; Glycosaminoglycans; Grant; Hippocampus (Brain); Hyaluronan; Hyaluronidase; Impaired cognition; Learning; Link; Macaca; Mediating; Memory; National Center for Research Resources; Neuronal Differentiation; Neurons; Pilot Projects; Primates; Principal Investigator; Research; Research Infrastructure; Resources; Self-Administered; Source; Stem cells; Testing; Transcript; United States National Institutes of Health; adult neurogenesis; alcohol exposure; cost; nerve stem cell; neurogenesis; nonhuman primate; receptor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. There is growing evidence that cognitive impairments associated with alcoholism are linked in part to alterations in adult neurogenesis in the subgranular zone (SGZ) of the hippocampus. Ethanol administration can infuence the proliferation, survival and differentiation of neural progenitor cells that would otherwise differentiate into neurons that contribute to learning and memory. Our preliminary data indicate that neurogenesis in the SGZ is regulated in part by the glycosaminoglycan hyaluronan (HA) and its transmembrane receptor, CD44. Degradation of HA or disruption of CD44 results in aberrant SGZ-derived progenitor cell proliferation and aberrant neuronal differentiation. We found that transcripts for hyaluronidases, enzymes that degrade HA, are increased in the hippocampi of cynomolgus macaques that self-administer ethanol. These data suggest that alcohol administration promotes HA degradation and that this degradation contributes to aberrant neurogenesis and cognitive impairment. Here, we aim to: (1) Test the hypothesis that ethanol administration leads to altered HA synthesis and degradation in the adult non-human primate SGZ through a mechanism that involves increased transcription of hyaluronidase genes; and (2) Test the hypothesis that altered HA levels and distribution in the SGZs of non-human primates that self-administer ethanol correlate with alterations in neural progenitor cell proliferation and survival. This pilot study will provide new clues about how alcohol consumption influences adult neurogenesis.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 越来越多的证据表明，与酗酒相关的认知障碍部分与海马颗粒下区（SGZ）成人神经发生的改变有关。乙醇给药可以影响神经祖细胞的增殖、存活和分化，否则神经祖细胞会分化成有助于学习和记忆的神经元。我们的初步数据表明 SGZ 的神经发生部分受到糖胺聚糖透明质酸 (HA) 及其跨膜受体 CD44 的调节。 HA 降解或 CD44 破坏导致 SGZ 来源的祖细胞增殖异常和神经元分化异常。我们发现，自我施用乙醇的食蟹猴海马中透明质酸酶（降解 HA 的酶）的转录物增加。这些数据表明，饮酒会促进 HA 降解，并且这种降解会导致神经发生异常和认知障碍。 在这里，我们的目标是：（1）检验乙醇给药通过涉及透明质酸酶基因转录增加的机制导致成年非人灵长类动物 SGZ 中 HA 合成和降解改变的假设； (2) 检验自我施用乙醇的非人类灵长类动物 SGZ 中 HA 水平和分布的改变与神经祖细胞的改变相关的假设 增殖和生存。这项试点研究将为了解饮酒如何影响成人神经发生提供新线索。