Role of GPR30 in Mediating Estrogen Effects on Neurons and Cognitive Performance

GPR30 在介导雌激素对神经元和认知表现的影响中的作用

• 批准号: 8240415
• 负责人: Rebecca L. Hammond
• 金额: $ 2.23万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240415
• 关键词: Accounting; Acetylcholine; Adverse effects; Age; Age-associated memory impairment; Agonist; Alzheimer' s Disease; Basal Nucleus of Meynert; Basic Science; Brain; Brain region; CREB1 gene; Cells; Clinical Research; Cognitive; Collecting Cell; Data; Dementia; Denervation; Development; Diagonal Band of Broca; Disease; Estradiol; Estrogen Receptor 1; Estrogen Receptors; Estrogens; Excision; Funding; Goals; Hippocampus (Brain); Immunohistochemistry; Immunotoxins; Impairment; Infusion procedures; Label; Lasers; Lesion; Medial; Mediating; Menopause; Messenger RNA; Microdialysis; Microscopy; Neurologic; Neurons; Ovarian; Ovariectomy; Pathway interactions; Performance; Positioning Attribute; Potassium; Prosencephalon; Public Health; Rattus; Relative (related person); Research Support; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Signal Transduction; Staining method; Stains; Testing; Therapeutic Agents; Time; Tissues; Woman; Work; aging brain; basal forebrain; basal forebrain cholinergic neurons; cholinergic; cholinergic neuron; cognitive function; follow-up; immunoreactivity; in vivo; lateral ventricle; mRNA Expression; novel; public health relevance; research study; response; uptake

DESCRIPTION (provided by applicant): This application is being completed to provide research support for a funded F31. Basic and clinical research suggests loss of estradiol following menopause may contribute to brain aging and increased risk of age-related cognitive decline and dementia. There is a great need for novel estrogenic compounds that confer positive cognitive effects without the risk of side effects. G-1 is a recently developed agonist for the novel transmembrane estrogen receptor (ER) GPR30 (Bologa et al., 2006). Activation of the GPR30 pathway is independent of either of the ER 1 or 2 pathways, raising the possibility of using G-1 as a novel estrogenic agent that lacks the risks associated with other estrogenic compounds. Previous work in our lab has shown that estradiol enhances cognitive performance in rats via effects on basal forebrain cholinergic neurons (Gibbs, 2002; Gibbs, 2007). We hypothesize that the effects of estradiol on cholinergic function and cognitive performance are mediated, in part, via effects on GPR30. The first goal of this proposal is to characterize GPR30 expression in the rat forebrain, focusing on co-expression by cholinergic neurons. Current experiments show extensive co-localization of GPR30 within cholinergic neurons in the septum, diagonal band of Broca, and nucleus basalis. GPR30 mRNA will be evaluated in these neurons using laser capture microscopy and RT-PCR. The second goal is to examine the functional effects of GPR30 activation on cholinergic neurons. Estradiol has been shown to induce activation of ERK and CREB in brain neurons and increase potassium-stimulated acetylcholine release in the hippocampus, consistent with an effect on basal forebrain cholinergic function (Gibbs et al., 1997; Levin, 2005). Our studies will evaluate rapid induction of pCREB and pERK within cholinergic neurons in response to systemic and intracerebroventricular infusions of G-1and other ER agonists. In vivo microdialysis is being used currently to evaluate the effects of G-1 and ER agonists on acetylcholine release in the hippocampus. The third goal is to test the ability of G-1 to enhance cognitive performance in ovariectomized rats comparable to the effects of estradiol. Effects of G-1 and estradiol will be compared with selective ER 1 and 2 agonists. This aim was recently completed, and G-1 was found to reverse the effects of ovariectomy on acquisition of a delayed matching to position T- maze task, similar to the effects of estradiol (Hammond et al., 2009). Current work is investigating the effects of GPR30 antagonism on this task. PUBLIC HEALTH RELEVANCE: Following menopause, women lose the neuroprotective effects of estrogen, placing them at an increased risk of developing age related cognitive decline and Alzheimer's disease, destructive neurological conditions for which no cure currently exists. Our analyses may broaden the understanding of a new pathway of estrogen signaling, laying the groundwork for the development of a new form of therapy for these diseases.

描述(由申请者提供)：本申请正在完成，旨在为F31基金提供研究支持。基础和临床研究表明，绝经后雌激素的丧失可能会导致大脑老化，并增加与年龄相关的认知能力下降和痴呆症的风险。非常需要新的雌激素化合物，既能产生积极的认知效果，又不会有副作用的风险。G-1是最近开发的一种新型跨膜雌激素受体(ER)GPR30的激动剂(Bologa等人，2006年)。GPR30通路的激活不依赖于ER1或ER2通路，这增加了将G-1用作一种新型雌激素制剂的可能性，这种新型雌激素缺乏与其他雌激素化合物相关的风险。我们实验室以前的工作表明，雌二醇通过影响基底前脑胆碱能神经元来提高大鼠的认知能力(Gibbs，2002；Gibbs，2007)。我们假设雌激素对胆碱能功能和认知功能的影响部分是通过对GPR30的影响来实现的。这项建议的第一个目标是表征GPR30在大鼠前脑中的表达，重点是胆碱能神经元的共同表达。目前的实验表明，GPR30广泛共存于隔核、Broca斜角带和基底核的胆碱能神经元中。将使用激光捕获显微镜和RT-PCR对这些神经元中的GPR30mRNA进行评估。第二个目标是研究GPR30激活对胆碱能神经元的功能影响。雌二醇已被证明可诱导脑神经元ERK和CREB的激活，并增加钾刺激的海马区乙酰胆碱的释放，这与对基底前脑胆碱能功能的影响一致(Gibbs等人，1997；Levin，2005)。我们的研究将评估全身和脑室注射G-1和其他ER激动剂后，胆碱能神经元中pCREB和PERK的快速诱导。在体微透析目前正被用来评估G-1和ER激动剂对海马乙酰胆碱释放的影响。第三个目标是测试G-1提高去卵巢大鼠认知能力的能力，与雌二醇的效果相当。G-1和雌二醇的作用将与选择性ER1和2激动剂进行比较。这一目标是最近完成的，G-1被发现逆转了卵巢切除对获得延迟匹配到位置T-迷宫任务的影响，类似于雌二醇的影响(Hammond等人，2009年)。目前的工作是研究GPR30拮抗对这一任务的影响。 公共卫生相关性：绝经后，女性失去雌激素的神经保护作用，使她们患上与年龄相关的认知能力下降和阿尔茨海默病的风险增加，这是一种破坏性的神经疾病，目前尚无治疗方法。我们的分析可能会拓宽对雌激素信号新途径的理解，为开发治疗这些疾病的新形式奠定基础。