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Characterization of a novel mouse model with enhanced TGF-Beta signaling in the ovary

卵巢中 TGF-Beta 信号传导增强的新型小鼠模型的表征

基本信息

批准号：
8968721
负责人：
Qinglei Li
金额：
$ 7.08万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8968721
关键词：
Belief Bioinformatics Cell Differentiation process Cell Proliferation Complement Data Development Disease Etiology Failure Female Female infertility Fertility Genes Goals Gonadal structure Hormonal Hormones Laboratories Malignant neoplasm of ovary Mediating Mission Modeling Molecular Mus National Institute of Child Health and Human Development Normal Cell Outcome Ovarian Ovarian Granulosa Cell Ovary Ovulation Pathway interactions Penetrance Phenotype Reproduction Research Role Series Sex Cord-Gonadal Stromal Tumors Signal Transduction Specificity Sterility TGFBR1 gene Testing Transforming Growth Factor beta Transforming Growth Factors Work base design folliculogenesis granulosa cell insight loss of function mouse model next generation sequencing novel novel diagnostics novel therapeutics programs public health relevance receptor reproductive reproductive function response tool transcriptomics treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The fundamental role of transforming growth factor ß (TGFß) superfamily signaling in reproduction has been witnessed over the past two decades. Despite enormous research efforts, the definitive role of TGFß signaling in the ovary remains unknown. Notably, over activation of TGFß signaling has been associated with the development of a number of diseases. Thus, there is a critical need to develop such a model to complement loss-of-function studies. Toward this goal, we have successfully generated a mouse model expressing a constitutively active TGFß type 1 receptor in the ovary (TGFBR1-CA). Strikingly, these mice were sterile and developed sex-cord stromal tumors. This application aims at validating this model, defining the consequence of over activation of TGFBR1 on folliculogenesis, and identifying novel genes and pathways regulating ovarian granulosa cell proliferation. Our central hypothesis is that over activation of TGFß signaling alters the proliferation and differentiation program of ovarian granulosa cells, leading to uncontrolled cell proliferation and reproductive failure. This hypothesis is based on our compelling preliminary data. We will test our hypothesis in a single aim which is to validate the mouse model with a constitutively active TGFBR1 in the ovary and identify novel genes and pathways regulating granulosa cell proliferation. This aim contains two sub-aims. Specific Aim #1a): Define the effect of over activation of TGFBR1 on follicular development, hormone profiles, and ovarian response to hormones. Specific Aim #1b): Identify molecular mechanisms underpinning TGFß signaling promoted ovarian granulosa cell proliferation. To accomplish this aim, we will perform a series of histological, cellular, hormonal, and transcriptomic analyses. The findings of the proposed studies are expected to establish a key role of TGFß signaling in promoting ovarian granulosa cell proliferation, highlighting the unique function of TGFß signaling in the female gonad. Thus, this unique mouse model holds promise to serve as an invaluable tool to study female infertility, ovarian cancer, and other pathological conditions, the etiology of which is associated with dysregulation of TGFß signaling.