Nicotine Receptors and COX2 in the Aging Brain

衰老大脑中的尼古丁受体和 COX2

基本信息

批准号：
8021012
负责人：
SCOTT Warren ROGERS
金额：
$ 23.42万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-05-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8021012
关键词：
Adult Age Aging Agonist Animals Anti-Inflammatory Agents Anti-inflammatory Astrocytes Biological Models Brain Congenic Mice Dissection Elderly Equilibrium Gene Expression Genetic Hippocampus (Brain)Inflammation Inflammation Mediators Inflammatory Interneuron function Interneurons Intervention Measures Metabolic Mouse Strains Neurons Nicotine Nicotinic Receptors Non-Steroidal Anti-Inflammatory Agents Outcome PPAR gamma PPARgamma2 PTGS2 gene Parvalbumins Phenotype Play Predisposition Process RXR Receptor Cell Regulation Relative (related person)Research Personnel Role Severities Signal Pathway Somatostatin System Therapeutic Therapeutic Intervention Work age related aged aging brain cholinergic cyclooxygenase 2 microchip novel programs receptor receptor expression receptor function response therapeutic target tissue culture transcription factor

项目摘要

DESCRIPTION (provided by applicant): Aging of the mammalian brain is accompanied by reduced expression of neuronal nicotinic acetylcholine receptors (nAChR), and decreased control of pro-inflammatory mechanisms. Our previous findings identified age-related and mouse strain-specific changes in nAChR expression by hippocampal interneurons (and astrocytes) and identified interactions with either the inflammatory mediator cyclooxygenase 2 (Cox2), or the RXR co-transcription factor, PPARgamma. We will now focus on genetic and cellular mechanisms contributing to these interactions. Completion of these studies will identify genetic mechanisms and possible therapeutic strategies for interventions that will promote stability of nAChR expression into advanced age. SPECIFIC AIM 1. Hypothesis: Interneuron subtypes, as defined by differential nAChR, somatostatin and Cox2/PPARgamma2 expression, vary in their relative susceptibility to age-related decline. Differential nAChR expression defines at least 4 interneuron subclasses in hippocampal CA1, but there are additional subtypes whose relative susceptibility to age-related loss will be determined. SPECIFIC AIM 2. Hypothesis: Intracellular pathways that signal neuronal responses to either nicotine or NSAIDs contribute to regulating nAChR expression in the aged brain, but converge to become antagonistic. Long-term NSAID administration promotes retention of nAChR expression into old age, but this is antagonized by co-administration of nicotine. A primary neuronal tissue culture model system will be used to define intracellular signaling pathways where these agents converge to produce antagonism. SPECIFIC AIM 3. Hypothesis: The efficacy of long-term administration of nicotine, Cox2 antagonists, and/or PPARgamma agonists on retaining nAChRalpha4 expression in aged animals is determined by strain-specific genetic background. Using newly generated congenic mouse lines, the importance of nAChR expression by astrocytes versus other components of the genetic background will be measured to identify strain-specific components of the nicotine and NSAID interaction, and determine if NSAIDs, working as PPARgamma agonists, promote retention of nAChRalpha4 expression in the aging brain.

描述（由申请人提供）：哺乳动物大脑的衰老伴随着神经元烟碱乙酰胆碱受体（NACHR）的表达降低，以及对促炎机制的控制降低。我们以前的发现确定了海马中神经元（和星形胶质细胞）中与年龄相关的NACHR表达中与小鼠菌株特异性的变化，并鉴定了与炎性介导剂环氧酶2（COX2）或RXR共同转录因子Ppargamma的相互作用。现在，我们将重点关注导致这些相互作用的遗传和细胞机制。这些研究的完成将确定遗传机制和干预措施的可能治疗策略，以促进NACHR表达在高级年龄中的稳定性。具体目标1。假设：中间的亚型，如差异NACHR，生长抑素和Cox2/ppargamma2的表达所定义，其相对易感性与年龄相关下降的敏感性有所不同。差异NACHR表达在海马CA1中定义了至少4个中间元亚类，但是还有其他亚型的相对易感性将确定与年龄相关的损失的相对敏感性。特定目的2。假设：信号对尼古丁或NSAID的神经元反应的细胞内途径有助于调节老年大脑中的NACHR表达，但会融合以拮抗。长期的NSAID给药促进了NACHR表达在老年中的保留，但这是通过尼古丁的共同给药来拮抗的。原发性神经组织培养模型系统将用于定义细胞内信号传导途径，在这些途径中，这些药物会融合产生拮抗作用。特定目的3。假设：尼古丁，COX2拮抗剂和/或ppargamma激动剂在衰老动物中保留nachralpha4表达的疗效取决于菌株特异性的遗传背景。使用新生成的异基因小鼠系，将测量星形胶质细胞与遗传背景的其他成分的NACHR表达的重要性，以鉴定尼古丁和NSAID相互作用的菌株特异性成分，并确定NSAID是否作为ppargamma激动剂起作用，促进鼻中pha44在脂肪脑中的静止。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nicotinic receptor Alpha7 expression during tooth morphogenesis reveals functional pleiotropy.

牙齿形态发生过程中烟碱受体 Alpha7 的表达揭示了功能多效性。

DOI：
10.1371/journal.pone.0036467
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Rogers,ScottW;Gahring,LoriseC
通讯作者：
Gahring,LoriseC

Nicotinic receptor alpha7 expression identifies a novel hematopoietic progenitor lineage.

DOI：
10.1371/journal.pone.0057481
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Gahring LC;Enioutina EY;Myers EJ;Spangrude GJ;Efimova OV;Kelley TW;Tvrdik P;Capecchi MR;Rogers SW
通讯作者：
Rogers SW

Prenatal ablation of nicotinic receptor alpha7 cell lineages produces lumbosacral spina bifida the severity of which is modified by choline and nicotine exposure.