Estrogen signaling transgenic mouse models

描述（由申请人提供）：雌激素受体α (ERa)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。ERa和ER是由两个基因编码的不同蛋白，在许多组织中表达。大多数研究集中在雌激素受体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所在。对于雌激素在非生殖器官、调节免疫调节、维持骨密度、心血管功能、行为、学习、记忆和脂肪形成中的作用，我们知之甚少。ERa和ER在发育和体内平衡过程中不是由相同的细胞类型表达的。然而，在雌激素调节的病理情况下，如乳腺癌，这两种er经常共表达。表达这两种er的乳腺癌比只表达ERa的乳腺癌预后更好。这两种er的基本生理功能已经通过基因缺失研究进行了检验。然而，很少有研究调查过表达ER的体内后果。小鼠中普遍存在的ERa过表达导致胚胎死亡，限制了研究，而多西环素诱导的ERa过表达是有用的，但受到组织特异性四环素反激活剂转基因小鼠系数量少的阻碍。此外，没有报道过表达ER¿的小鼠模型。缺乏稳健和灵活的小鼠模型来条件过表达ERa或ER¿限制了雌激素信号研究在多个领域的进展。因此，本课题的目标是通过Cre重组酶依赖的方式产生不同水平过表达ERa或ER¿的转基因小鼠，以研究ER在体内的功能并建立ER过表达病理模型。

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.