Estrogen signaling transgenic mouse models

雌激素信号传导转基因小鼠模型

基本信息

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
项目类别：
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

项目摘要

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.

描述（由适用提供）：雌激素受体α（ERA）和β（erTA）是核受体超家族的成员，并介导了进化的作用。这些受体参与了许多多样化的身体过程，还参与了包括癌症在内的病理状况。 ERA和ER¿是由两个基因编码的独特蛋白质，并在许多组织中表达。大多数研究都集中在ERS在男性和女性生殖道的发展和功能中的作用，这是我们实验室的利益。关于雌激素在非生殖器官中的作用知之甚少，控制免疫调节，维持骨密度，心血管功能，行为，学习，记忆和脂肪形成。在开发和稳态期间，ERA和ER¿并未用相同的细胞类型表达。但是，在雌激素调节的病理状况（例如乳腺癌）中，这两个ER都经常共表达。表达这两种人的乳腺癌的预后都比那些只表达时代的乳腺癌更好。通过基因缺失研究已经检查了两个ER的基本生理功能。但是，很少有研究研究ER过表达的体内后果。小鼠中ERA的无处不在过表达导致胚胎致死性，限制研究，而强力霉素诱导的ERA的过表达是有用的，但是由于组织特异性四环素经激活的反式激活驱动器少量的阻碍。此外，没有报道过ER？的小鼠模型。缺乏可用于ERA或ER的条件过表达的健壮和柔性小鼠模型限制了多个领域的雌激素信号研究的进展。因此，该建议的目的是生成可以以CRE重组酶依赖性方式在不同级别上过表达时代或ER的转基因小鼠，以研究体内和模型ER过表达病理的ER功能。公共卫生相关性：雌激素是一种通常控制许多不同人体功能但也会影响威胁生命疾病的进展，包括乳腺癌和前列腺癌的进展。该项目将开发新型的雌激素受体转基因小鼠模型，以激活不同器官中雌激素调节的基因表达，以研究由雌激素控制的潜水员物理和病理过程。