Rat Models for Sex Steroid Action

描述(申请人提供)：合适的动物模型促进生物医学科学中的科学研究。大鼠是研究生理过程的有价值的模型，也是制药和农化行业使用的主要临床前动物模型系统。雌激素和孕激素是影响整个生物体生理的关键荷尔蒙。这些激素通过与特定配体激活的转录因子的物理相互作用作用于它们的细胞靶标，以调节基因转录。雌二醇通过雌激素受体α(ESR1)和雌激素受体β(ESR2)结合并传递信号，而孕酮通过孕激素受体(PGR)传递信号。性类固醇激素的研究一直是开发治疗各种疾病和健康相关疾病的治疗方法的核心。关键调控基因突变的动物模型的出现，极大地促进了对特定细胞信号通路的研究。对于雌激素和孕激素信号通路来说，这当然是正确的。ESR1、Esr2和PGR基因座零突变的小鼠已经为雌激素和孕激素的生理作用提供了重要的见解。然而，小鼠在某些研究领域有局限性，特别是与生理学和药理学相关的领域，在这些领域，大鼠已被证明是一个更好的动物模型。在大鼠的基因操作方面已经取得了相当大的进展。其中包括应用锌指核酸酶(ZFN)基因组编辑来产生老鼠敲除菌株。在这个应用中，我们建议建立和表征性类固醇激素作用的大鼠模型。我们将独立瞄准ESR1、ESR2和Pgr2。我们对突变大鼠品系的特征将集中在与雌性生殖道相关的表型上。雌激素和孕激素信号中断的大鼠将为生物医学科学家在一系列学科中提供新的工具，包括癌症生物学、生殖、女性健康、环境健康、新陈代谢、免疫学、神经科学和心血管生物学。这些新的动物模型将向研究界提供。

DESCRIPTION (provided by applicant): Appropriate animal models facilitate scientific investigation in the biomedical sciences. The rat is a valuable model for studying physiological processes and is the dominant pre-clinical animal model system used by the pharmaceutical and agro-chemical industries. Estrogens and progestins are key hormones affecting the physiology of the entire organism. These hormones act on their cellular targets through physical interactions with specific ligand-activated transcription factors to regulate gene transcription. Estradiol binds and signals through estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2), while progesterone signals through the progesterone receptor (PGR). Research on sex steroid hormones has been central to the development of therapeutics for the treatment of a variety of diseases and health related conditions. Research on the involvement of specific cell signaling pathways have benefitted tremendously from the availability of animal models possessing mutations in critical regulatory genes. This is certainly true for estrogen and progestin signaling pathways. Mice with null mutations at the Esr1, Esr2, and Pgr loci have provided significant insights about the physiology of estrogen and progestin actions. However, the mouse has limitations for some fields of investigation, especially those related to physiology and pharmacology where the rat has proven to be a much better animal model. Considerable advances have been made in genetic manipulation of the rat. These include the application of zinc finger nuclease (ZFN) genome editing to produce rat knock out strains. In this application, we propose to generate and characterize rat models for sex steroid hormone action. We will independently target Esr1, Esr2, and Pgr2. Our characterization of the mutant rat strains will focus on phenotypes associated with the female reproductive tract. Rats possessing disruptions in estrogen and progesterone signaling will provide new tools for biomedical scientists in a range of disciplines, including cancer biology, reproduction, women's health, environmental health, metabolism, immunology, neurosciences, and cardiovascular biology. These new animal models will be made available to the research community.