SGER: Development of a Mouse With Inducible Estrogen Receptor Alpha Function

雌激素是一种类固醇激素，在整个生命周期中都很重要。它参与的功能包括细胞迁移，骨骼发育，生殖发育，神经发生，心脏功能，甚至神经可塑性和认知，以及其作为生殖激素的众所周知的作用。雌激素通过两种主要的已知分子受体α（ER-α）和β（ER-β）在细胞水平起作用。这些受体是促进细胞生长和增殖的转录因子。从对基因敲除（KO）小鼠的研究中已知ER-α受体是参与生殖社会行为和非生殖行为如探索行为、学习和记忆的主要受体，并且在发育中具有重要功能。这个SGER项目使用一种新的方法来创建一个“诱导型”基因KO小鼠品系，而不是目前可用的简单敲除。 诱导性敲除的概念并不新鲜，但对于在大脑中具有如此广泛分布和功能重要性的任何类固醇受体，还没有开发出可逆性敲除。ER-α的可诱导基因表达将允许可逆地操纵这种类固醇受体功能，因此在发育的不同阶段和成人中不仅关闭基因表达，而且再次打开基因表达，从而允许探索生命中是否存在这种重要受体功能的不同“关键时期”。 这是一个高影响/高风险项目，因为结果尚不明确，但成功的潜在影响是广泛的。 如果成功，结果将导致对类固醇激素的时间依赖性功能的进一步研究，并将对神经内分泌学以外的发育生物学和认知神经科学等领域产生重大影响。该项目还为研究生提供了宝贵的培训经验，将分子生物学与神经内分泌学联系起来。

Estrogen is a steroid hormone that is important throughout the lifespan. It is involved in functions including cell migration, bone development, reproductive development, neurogenesis, heart function and even neural plasticity and cognition, as well as its well-known actions as a reproductive hormone. Estrogen acts at the cellular level through two main known molecular receptors, alpha (ER-a) and beta (ER-B). These receptors are transcription factors that promote cell growth and proliferation. The ER-a receptor is known from studies on genetic knockout (KO) mice to be the major receptor involved in reproductive social behaviors, and in non-reproductive behaviors such as exploratory behavior, learning and memory, as well has having an important function in development. This SGER project uses a novel approach to create an 'inducible' genetic KO mouse strain, rather than the simple knockouts currently available. The concept of an inducible knockout is not new, but there has been no reversible knockout developed for any of the steroid receptors, which have such widespread distribution and functional importance in the brain. The inducible genetic expression of ER-a will allow this steroid receptor function to be manipulated reversibly, and so turn the gene expression not only off, but also on again, during different stages of development and in adults, allowing exploration of whether there are distinct 'critical periods' in life for the function of this important receptor. This is a high-impact/high-risk project because the outcome is not clear, but the potential impact of success is wide-ranging. If successful, the results will lead to further studies on time-dependent functions of steroid hormones, and will have a high impact extending beyond neuroendocrinology into the areas such as developmental biology and cognitive neuroscience. The project also provides a valuable training experience for a graduate student bridging molecular biology with neuroendocrinology.