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

大脑在整个生命过程中的功能适应围绕着它通过与环境刺激相互作用形成新的神经连接而进行自我重组的能力。这种刺激包括循环激素水平的变化，如雌激素17β-雌二醇，以及雄激素，如睾酮，可在酶作用下转化为17β-雌二醇。人们普遍认为，17β-雌二醇是大脑中最活跃的雌激素，而其研究较少的异构体17α-雌二醇是一种化合物，每个原子的数量和类型都相同，但排列方式不同，通常被认为在生物上没有活性。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，与卵巢来源的17β-雌二醇不同，17α-雌二醇实际上是在大脑中合成的，可能对成年海马区的神经发生[通过细胞分裂形成新的神经元]等神经功能至关重要，海马区是大脑中与学习、记忆和情绪调节有关的区域。根据质谱仪的测定，成年小鼠大脑中17α-雌二醇的含量似乎明显高于17β-雌二醇的含量。质谱仪通过将一个分子或化合物分解成其组成部分来确定其结构。17α-雌二醇在大脑中的作用在很大程度上仍不清楚。利用脑细胞和来自大脑17α-雌二醇水平非常低或升高的小鼠品系的完整小鼠的培养，将从(I)神经发生、(Ii)与生长因子BDNF(脑源性神经营养因子)的相互作用以及(Iii)控制情绪的能力方面比较17α-雌二醇、17β-雌二醇和芝麻油的作用。这项研究的完成将提供一幅图像，了解17α-雌二醇和芝麻油如何在大脑中发挥作用，以及这些激素如何影响学习和记忆以及影响情绪。这项研究将使细胞和分子生物学家、神经科学家和生物化学家能够进行跨学科的合作。对本科生、研究生和研究生研究助理(包括代表人数不足的少数群体和妇女)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，通过指导经验较少的研究人员和本科生来获得有价值的教学和指导技能。

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.