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Impact of Estrogens and Menopause on Interacting Monoamine Neurotransmitters in t

雌激素和更年期对相互作用的单胺神经递质的影响

基本信息

批准号：
8705338
负责人：
ROBERT B GIBBS
金额：
$ 19.25万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8705338
关键词：
Accounting Affect Age-associated memory impairment Aging Agonist Amino Acid Neurotransmitters Amino Acids Animal Model Binding Biochemical Pathway Biological Blood capillaries Brain Brain region Choline O-Acetyltransferase Clinical Cognitive Corpus striatum structure Coupled Critical Pathways DNA Data Diestrus Disease Dopamine Electrodes Estradiol Estrogen Receptors Estrogen Therapy Estrogens Flame Ionization G-Protein-Coupled Receptors Gas Chromatography Genetic Transcription Goals Heart Arrest High Pressure Liquid Chromatography Hippocampus (Brain)Hormone replacement therapy Hormones Individual Laboratories Lead Mediating Membrane Menopause Metabolic Modeling Molecular Weight Neurons Neurotransmitters Nuclear Receptors Operative Surgical Procedures Outcome Ovarian Ovariectomy Oxidation-Reduction Oxidative Stress Pathway interactions Performance Play Proestrus Rattus Relative (related person)Role Selective Estrogen Receptor Modulators Serotonin Stroke Surgical Models System Technology Testing Tissues Woman capillary cholinergic neuron clinically relevant cognitive function detector frontal lobe improved interest metabolomics middle age monoamine neurochemistry neuroprotection prevent public health relevance receptor response young adult

项目摘要

DESCRIPTION (provided by applicant): Our goal is to understand mechanisms by which estrogens affect the brain and cognitive performance. Estrogens have many beneficial effects in the brain; however, the mechanisms by which estrogens mediate these effects are in many ways unknown. We hypothesize that these effects reflect in large part effects on multiple interacting neurotransmitter pathways in specific brain regions. In particular, we hypothesize that loss of ovarian function results in multiple and simultaneous decreases in specific monoaminergic pathways in the brain, and that selective agonists acting at specific estrogen receptors can reverse these effects and restore the neurotransmitter pathways to a physiologically normal state. Over the past decade, Dr. Yao's (co-PI) laboratory has focused on developing technologies to quantify multiple low-molecular weight redox-active compounds (e.g., monoamines, monoamine metabolites, amino acids, markers of oxidative stress, etc...) in biological tissues. This is accomplished using state-of-the-art high-pressure liquid chromatography coupled with a 16-channel Coulometric Multi-Electrode Array System (HPLC-CMEAS) and capillary gas chromatography with a flame-ionization detector (GC-FID). The power of this technology is the ability to assess multiple metabolites from different biochemical pathways simultaneously in the picomol range. Using animal models of both surgical and natural menopause, we will apply this technology to evaluate the effects of 'menopause' and treatment with selective estrogen receptor agonists on multiple neurotransmitter pathways within specific brain regions. Models of menopause will include ovariectomy (a model of surgical menopause), and treatment with 4-vinylcyclohexene diepoxide (VCD; a model of natural menopause). Estrogen treatments will include 17ss-estradiol (E2), G-1 (a selective GPR30 agonist), PPT (a selective ER¿ agonist) and DPN (a selective ERss agonist) administered continuously sc. at 5 ¿g/day for 1 week or six weeks following loss of ovarian function. Tissues from the hippocampus, frontal cortex, and striatum will be dissected and analyzed for levels of monoamines, monoamine metabolites, amino acid neurotransmitters, and choline acetyltransferase (a marker of cholinergic neurons). This study will provide a detailed description of the changes in neurochemically relevant compounds that occur in specific regions of the brain, in two models of menopause, in response to selective hormone treatments. The studies also will be the first to evaluate the effects of a selective GPR30 agonist on these targets and to compare them with the effects of selective ER¿ and ERss agonists. The findings will provide a much clearer understanding of the neurochemical changes associated with different types of menopause and will lead to better strategies for approaching estrogen therapy in women.

描述（由申请人提供）：我们的目标是了解雌激素影响大脑和认知能力的机制。雌激素对大脑有许多有益的作用。然而，雌激素介导这些作用的机制在许多方面尚不清楚。我们假设这些影响在很大程度上反映了对特定大脑区域中多种相互作用的神经递质通路的影响。特别是，我们假设卵巢功能的丧失会导致大脑中特定单胺能途径的多重同时减少，而作用于特定雌激素受体的选择性激动剂可以逆转这些影响并将神经递质途径恢复到生理正常状态。在过去的十年中，姚博士（共同负责人）实验室致力于开发量化生物组织中多种低分子量氧化还原活性化合物（例如单胺、单胺代谢物、氨基酸、氧化应激标记物等）的技术。这是通过使用最先进的高压液相色谱结合 16 通道库仑多电极阵列系统 (HPLC-CMEAS) 和配备火焰离子化检测器的毛细管气相色谱 (GC-FID) 来实现的。该技术的强大之处在于能够在皮摩尔范围内同时评估来自不同生化途径的多种代谢物。使用手术和自然绝经的动物模型，我们将应用这项技术来评估“更年期”和选择性雌激素受体激动剂治疗对特定大脑区域内多个神经递质途径的影响。更年期模型包括卵巢切除术（手术绝经模型）和 4-乙烯基环己烯二环氧化物（VCD；自然绝经模型）治疗。雌激素治疗将包括连续皮下施用的17β-雌二醇(E2)、G-1(选择性GPR30激动剂)、PPT(选择性ERβ激动剂)和DPN(选择性ERβ激动剂)。卵巢功能丧失后，每天 5 克，持续 1 周或六周。将解剖海马体、额叶皮层和纹状体的组织，并分析单胺、单胺代谢物、氨基酸神经递质和胆碱乙酰转移酶（胆碱能神经元的标记）的水平。这项研究将详细描述在两种更年期模型中大脑特定区域发生的神经化学相关化合物对选择性激素治疗的反应。这些研究也将首次评估选择性 GPR30 激动剂对这些靶标的作用，并将其与选择性 ER¿ 和 ERss 激动剂的作用进行比较。这些发现将使我们更清楚地了解与不同类型的更年期相关的神经化学变化，并将为女性雌激素治疗提供更好的策略。