Nicotinic Receptors and COX2 in the Aging Brain

衰老大脑中的烟碱受体和 COX2

• 批准号: 6629863
• 负责人: SCOTT Warren ROGERS
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629863
• 关键词: aging; antiinflammatory agents; cholinergic receptors; genetic transcription; hippocampus; immunocytochemistry; immunoprecipitation; laboratory mouse; longitudinal animal study; microarray technology; neural degeneration; neural transmission; nicotinic receptors; prostaglandin endoperoxide synthase; receptor expression; western blottings

DESCRIPTION(From applicant's abstract): Our goal is to understand the decline in cholinergicneurotransmission associated with age and to determine if intervention with exogenous aaents such as cholinergic agonists or anti-inflammatories modifies this age-related process. The overall hypothesis to be tested is: Long-term oral administration of nicotine and/or non-steroidal anti-inflammatories to adult CBA/J mice provides protection against age-related loss and/or changes in nicotinic cholinergic receptor expression and function. We have developed a mouse model (Rogers et al., J. Neurosci. 18:4825-4832, 1998) that reliably reflects age-related decline in neuronal nicotinic acetylcholine receptor (nAChR) expression (i.e., nAChRa4 subunit) and shown that long-term (1 year) oral nicotine delivery slows this decline. No data are available regarding other nAChR subunit expression in the aging mouse brain, or how the brain may compensate for the changes. Notably, the nAChRa4 expressing cholinergic neurons in CAl that are diminished in the aged brain also constitutively express cyclooxygenase-2 (COX2), a target of non-steroidal anti-inflammatories (NSAIDs) that have been suggested to be neuroprotective. The focus of this proposal is to examine the influence of long-term (1-year) oral nicotine, Cox-2 preferring NSAIDs or both on the process of age-related change in nAChA expression and function in the CBA mouse brain through answering three basic questions. Specific Aim 1: Do age-related changes in the expression of multiple nicotinic acetyicholine receptor (nAChR) subunits occur and are these changes modified by long-term nicotine administration? Specific Aim 2: Does inhibition of cyclooxygenase 2 by non-steroidal anti-inflammatory drugs (NSA!Ds) impact age-related alterations in nAChR subunit expression? Finally, since aging influences many cellular functions including the ability to respond to inflammatory agents, we will ask in Specific Aim 3 using microarray chip analysis; Do these treatments contribute to maintaining normal transcriptional responses by the brain?

描述（来自申请人的摘要）： 我们的目标是了解胆碱能透射的下降 与年龄相关，并确定是否与外源性A的干预此类干预 作为胆碱能激动剂或抗炎药可以修饰与年龄有关的 过程。要测试的总体假设是：长期口服 成人CBA/J小鼠的尼古丁和/或非甾体类抗炎 提供防止与年龄有关的损失和/或烟碱变化的保护 胆碱能受体的表达和功能。我们已经开发了鼠标模型 （Rogers等，J。Neurosci。18：4825-4832，1998）可靠地反映 与年龄相关的神经元烟碱乙酰胆碱受体（NACHR）的下降 表达（即nACHRA4亚基），并表明长期（1年）口头 尼古丁的递送减慢了这种下降。没有有关其他的数据 NACHR亚基在衰老的小鼠大脑中或大脑如何 补偿变化。值得注意的是，nACHRA4表达胆碱能神经元 在老年大脑中减少的CAL中，还组成型表达 环氧酶-2（COX2），非甾体抗炎（NSAID）的靶标 已建议是神经保护作用。该提议的重点是 为了检查长期（1年）口服尼古丁的影响，COX-2更喜欢 NSAID或在NACHA表达与年龄相关的变化过程中 通过回答三个基本问题，在CBA鼠标大脑中发挥作用。 具体目标1： 在多种烟碱乙酰氨酸的表达中发生与年龄相关的变化 受体（NACHR）亚基发生，这些变化是否通过长期改变 尼古丁给药？特定目标2：是否抑制环氧合酶2 非甾体类抗炎药（NSA！ds）影响与年龄有关的改变 在NACHR亚基表达中？最后，由于衰老会影响许多细胞 我们将询问包括对炎症剂的反应能力在内的功能 在特定目标3中，使用微阵列芯片分析；进行这些治疗 有助于维持大脑正常的转录反应？