SGER: 17alpha-estradiol: a novel endogenous mitogen and anti-depressant in the brain

SGER：17α-雌二醇：一种新型内源性有丝分裂原和大脑抗抑郁药

• 批准号: 0710796
• 负责人: C. Dominique Toran-Allerand
• 金额: $ 20万
• 依托单位: Columbia University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0710796&HistoricalAwards=false
• 关键词: SGER; 17alpha; estradiol; novel; endogenous

Functional adaptation of the brain throughout life centers around its ability to reorganize itself through the formation of new neural connections made possible by interactions with environmental stimuli. Such stimuli include changing levels of circulating hormones, such as the estrogen 17beta-estradiol, and androgens, such as testosterone, that can be converted enzymatically to 17beta-estradiol. It is generally accepted that 17beta-estradiol is the estrogen most active in the brain, while its little studied isomer, 17alpha-estradiol, a chemical compound with the same number and type of each atom but in a different arrangement, is generally considered biologically inactive. New data suggests that this viewpoint may be inaccurate and the role of this 17-alpha-estradiol in the nervous system needs to be re-evaluated. Accumulating evidence indicates that 17alpha-estradiol, unlike 17beta-estradiol which is of ovarian origin, is actually synthesized in the brain and may be critical for neural functions such as neurogenesis [new neuron formation through cell division] in the adult hippocampus, a brain region implicated in learning, memory and regulation of mood. It appears that 17alpha-estradiol is significantly higher in the brains of adult mice of both sexes than that of 17beta-estradiol, as determined by mass spectrometry, which determines the structure of a molecule or compound by fragmenting it into its component parts. The role of 17alpha-estradiol in the brain has remained largely unknown. Using cultures of brain cells and intact mice from mouse strains with either very low or elevated brain levels of 17alpha-estradiol, the roles of 17alpha-estradiol, 17beta-estradiol and sesame oil will be compared with respect to (i) neurogenesis, (ii) interactions with the growth factor BDNF (brain-derived neurotrophic factor), and (iii) ability to control moods. Completion of this research will provide a picture of how 17alpha-estradiol and sesame oil may act in the brain and how these hormones impact learning and memory and influence mood. This research will enable collaborations across disciplines with cell and molecular biologists, neuroscientists and biochemists. Training for undergraduate, graduate, and post-graduate research assistants (including underrepresented minorities and women) will be an integral aspect of the project. This project will also train future faculty, who are not yet independent faculty members themselves to obtain valuable teaching and mentoring skills by supervising less experienced researchers and undergraduate students.

在整个生命过程中，大脑的功能适应围绕着它通过与环境刺激的相互作用形成新的神经连接来重组自己的能力。这些刺激包括改变循环激素的水平，如雌激素17 β-雌二醇，和雄激素，如睾酮，可以酶促转化为17 β-雌二醇。人们普遍认为17 β-雌二醇是大脑中最活跃的雌激素，而其很少研究的异构体，17 α-雌二醇，一种具有相同数量和类型的每个原子但排列不同的化合物，通常被认为是生物学上不活跃的。新的数据表明，这种观点可能是不准确的，这种17-α-雌二醇在神经系统中的作用需要重新评估。越来越多的证据表明，17 α-雌二醇，不像17 β-雌二醇是卵巢来源的，实际上是在大脑中合成的，可能对神经功能至关重要，如成年海马体中的神经发生[通过细胞分裂形成新的神经元]，这是一个涉及学习，记忆和情绪调节的大脑区域。看来，17 α-雌二醇是显着高于17 β-雌二醇在成年小鼠的大脑中的性别，如确定的质谱法，它确定了分子或化合物的结构，通过将其分解成其组成部分。17 α-雌二醇在大脑中的作用在很大程度上仍然未知。使用脑细胞培养物和来自脑内17 α-雌二醇水平极低或升高的小鼠品系的完整小鼠，比较17 α-雌二醇、17 β-雌二醇和芝麻油在（i）神经发生、（ii）与生长因子BDNF（脑源性神经营养因子）的相互作用和（iii）控制情绪的能力方面的作用。这项研究的完成将提供17 α-雌二醇和芝麻油如何在大脑中起作用以及这些激素如何影响学习和记忆以及影响情绪的图片。这项研究将使跨学科的合作与细胞和分子生物学家，神经科学家和生物化学家。对本科生、研究生和研究生研究助理（包括代表性不足的少数民族和妇女）的培训将是该项目的一个组成部分。该项目还将培训未来的教师，他们本身还不是独立的教师，通过指导经验不足的研究人员和本科生来获得宝贵的教学和指导技能。