Estrogen signaling transgenic mouse models

描述（由申请人提供）：雌激素受体α（ER α）和β（ER <$）是核受体超家族的成员，介导雌激素的作用。这些受体参与许多不同的生理过程，但也参与病理条件，包括癌症。ER α和ER <$是由两个基因编码的不同蛋白质，并在许多组织中表达。大多数研究都集中在ER在男性和女性生殖道发育和功能中的作用，这是我们实验室的兴趣。关于雌激素在非生殖器官中的作用，调节免疫调节，维持骨密度，心血管功能，行为，学习，记忆和脂肪形成的作用知之甚少。ER α和ER β在发育和稳态过程中不被相同的细胞类型表达。然而，在雌激素调节的病理情况下，如乳腺癌，两种ER经常共表达。表达两种ER的乳腺癌比仅表达ER α的乳腺癌具有更好的预后。这两个ER的基本生理功能已通过基因缺失研究进行了研究。然而，很少有研究调查ER过表达的体内后果。ER α在小鼠中的普遍过度表达导致胚胎致死，限制了研究，而多西环素诱导的ER α过度表达是有用的，但受到少量组织特异性四环素反式激活因子转基因小鼠系的阻碍。此外，还没有关于ER过表达的小鼠模型的报道。缺乏用于ER α或ER？条件性过表达的稳健和灵活的小鼠模型限制了多个领域雌激素信号传导研究的进展。因此，本提案的目的是产生能够以Cre重组酶依赖性方式在不同水平过表达ER α或ER β的转基因小鼠，以研究体内ER功能并模拟ER过表达病理。

DESCRIPTION (provided by applicant): Estrogen receptor alpha (ERa) and beta (ER¿) are members of the nuclear receptor superfamily and mediate the actions of estrogens. These receptors are involved in numerous and diverse physiological processes but also pathological conditions, including cancer. ERa and ER¿ are distinct proteins encoded by two genes, and expressed in many tissues. Most studies have focused on the role of ERs in male and female reproductive tract development and function, the interest of our laboratory. Little is known about the actions of estrogens in non-reproductive organs, regulating immune modulation, maintenance of bone density, cardiovascular function, behavior, learning, memory, and adipogenesis. ERa and ER¿ are not expressed by the same cell types during development and homeostasis. However, in estrogen-regulated pathological situations, such as breast cancer, both ERs are frequently co-expressed. Breast cancers that express both ERs have a better prognosis than those that express only ERa. The essential physiological functions of both ERs have been examined by gene deletion studies. However, few studies have investigated the in vivo consequences of ER over-expression. Ubiquitous over-expression of ERa in mice led to embryo lethality, limiting studies, whereas doxycycline-inducible over-expression of ERa was useful, but hindered by the small number of tissue-specific tetracycline transactivator transgenic mouse lines. Furthermore, no mouse models for ER¿ over-expression have been reported. The lack of robust and flexible mouse models for conditional over-expression of ERa or ER¿ is limiting progress in estrogen signaling research in multiple fields. Therefore, the objective of this proposal is to generate transgenic mice that can over-express ERa or ER¿ at different levels in a Cre recombinase-dependent manner to investigate ER function in vivo and model ER over-expression pathologies.