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；然而，雌激素介导这些影响的机制在很多方面都是未知的。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途径的影响，特别是，我们发现卵巢功能的丧失会导致大脑中特定单胺能途径的多种且同时减少。作用于特定雌激素受体的激动剂可以逆转这些效应，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）实验室一直致力于开发量化多种低分子量氧化还原活性的技术。这是通过使用最先进的高压液相色谱来完成的。与 16 通道库仑多电极阵列系统 (HPLC-CMEAS) 和带有火焰离子化检测器的毛细管气相色谱 (GC-FID) 相结合，该技术的强大之处在于能够同时评估来自不同生化途径的多种代谢物。在皮摩尔范围内，我们将使用手术和自然绝经的动物模型来评估“绝经”和选择性雌激素受体激动剂治疗对多种疾病的影响。更年期模型将包括卵巢切除术（手术绝经模型）和 4-乙烯基环己烯双环氧化合物（VCD；自然绝经模型）治疗将包括 17ss-雌二醇 (E2)、G。 -1（选择性 GPR30 激动剂），PPT（选择性 ER¿激动剂）和 DPN（选择性 ERss 激动剂）以 5 ¿ g/天，持续 1 周或 6 周，在卵巢功能丧失后，将解剖并分析海马、额叶皮质和纹状体的单胺、单胺代谢物、氨基酸神经递质和胆碱乙酰转移酶（胆碱能标记物）的水平。这项研究将详细描述在两个模型中大脑特定区域发生的神经化学相关化合物的变化。这些研究也将首次评估选择性 GPR30 激动剂对这些靶点的影响，并将其与选择性 ER 的效果进行比较。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，并为女性制定更好的雌激素治疗策略。