Estrogen signaling transgenic mouse models

雌激素信号传导转基因小鼠模型

• 批准号: 8248960
• 负责人: Richard R Behringer
• 金额: $ 19.75万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8248960
• 关键词: Area; Behavior; Biological Assay; Bone Density; Cardiovascular Physiology; Cardiovascular system; Cells; Communities; Development; Disease; Doxycycline; Embryo; Epitopes; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Female; Gastrointestinal tract structure; Gene Deletion; Gene Expression; Gene Targeting; Gene Transfer Techniques; Genes; Genetic; Genetically Engineered Mouse; Homeostasis; Hormones; Immune; Laboratories; Lead; Learning; Life; Liver; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Memory; Methods; Mus; Neuraxis; Nuclear Receptors; Organ; Pathologic Processes; Pathology; Physiological; Physiological Processes; Positioning Attribute; Proteins; Reporting; Reproductive Biology; Reproductive system; Research; Research Personnel; Role; Screening procedure; Series; Signal Transduction; Testing; Tetracyclines; Tissues; Trans-Activators; Transgenes; Transgenic Mice; Transgenic Organisms; Variant; cell type; chromosome loss; embryonic stem cell; flexibility; immunoregulation; in vivo; in vivo Model; innovation; interest; lipid biosynthesis; male; malignant breast neoplasm; member; mouse model; novel; outcome forecast; receptor; recombinase; reproductive; tool; transgene expression; tumor progression; zygote

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. PUBLIC HEALTH RELEVANCE: Estrogen is a hormone that normally controls many different body functions but can also influence the progression of life-threatening diseases, including breast and prostate cancer. This hormone acts through receptors that regulate gene expression. This project will develop novel estrogen receptor transgenic mouse models to activate estrogen-regulated gene expression in different organs to study the diverse physiological and pathological processes controlled by estrogen.

说明(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，调节雌激素的作用。这些受体参与了许多不同的生理过程，但也参与了包括癌症在内的病理情况。Era和ER是由两个基因编码的不同蛋白质，在许多组织中都有表达。大多数研究都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。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、记忆和脂肪生成的作用知之甚少。在发育和动态平衡过程中，Era和ER不是由相同类型的细胞表达的。然而，在雌激素调节的病理情况下，如乳腺癌，这两个ER经常是共表达的。同时表达两种ER的乳腺癌比只表达ERA的乳腺癌预后更好。通过基因缺失研究，研究了这两种内质网的基本生理功能。然而，很少有研究研究ER过度表达在体内的后果。在小鼠中普遍存在的ERA过度表达导致胚胎死亡，限制了研究，而多西环素诱导的ERA过度表达是有用的，但受到少数组织特异性四环素反式激活剂转基因小鼠的阻碍。此外，还没有关于ER？过度表达的小鼠模型的报道。缺乏健壮和灵活的小鼠模型来条件地过度表达ERA或ER，限制了雌激素信号在多个领域的研究进展。因此，本研究的目的是建立能够以Cre重组酶依赖的方式在不同水平过度表达ERa或ER的转基因小鼠，以研究ER在体内的功能，并建立ER过度表达的病理模型。 与公共健康相关：雌激素是一种荷尔蒙，通常控制许多不同的身体功能，但也可以影响威胁生命的疾病的进展，包括乳腺癌和前列腺癌。这种荷尔蒙通过调节基因表达的受体起作用。本项目将建立新型雌激素受体转基因小鼠模型，以激活雌激素调控基因在不同器官中的表达，研究雌激素调控的多种生理和病理过程。