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

 描述(由申请人提供)：在过去的二十年里，转化生长因子(转化生长因子)超家族信号在生殖中的基本作用已经被见证。尽管进行了大量的研究，但转化生长因子？信号在卵巢中的确切作用仍不清楚。值得注意的是，转化生长因子B信号的过度激活与许多疾病的发生有关。因此，迫切需要开发这样一个模型来补充功能丧失研究。为了实现这一目标，我们成功地建立了一种在卵巢中表达具有结构性活性的转化生长因子β1型受体的小鼠模型(TGFBR1-CA)。引人注目的是，这些小鼠是不育的，并患上了性索间质肿瘤。本研究旨在验证该模型，明确TGFBR1过度激活对卵泡发生的影响，并寻找调控卵巢颗粒细胞增殖的新基因和新途径。我们的中心假设是，过度激活的转化生长因子？信号改变了卵巢颗粒细胞的增殖和分化程序，导致细胞不受控制的增殖和生殖失败。这一假设是基于我们令人信服的初步数据。我们将在一个单一的目标上验证我们的假设，即验证卵巢中具有结构性活性的TGFBR1的小鼠模型，并识别调控颗粒细胞增殖的新基因和新途径。这一目标包含两个子目标。具体目标#1a)：明确过度激活TGFBR1对卵泡发育、激素谱和卵巢对激素的反应的影响。具体目标#1b)：确定支持转化生长因子B信号促进卵巢颗粒细胞增殖的分子机制。为了实现这一目标，我们将进行一系列的组织学、细胞学、激素和转录分析。这些研究结果有望确定转化生长因子？？信号在促进卵巢颗粒细胞增殖中的关键作用，突出转化生长因子？？信号在女性性腺中的独特功能。因此，这一独特的小鼠模型有望成为研究女性不孕不育、卵巢癌和其他病理条件的宝贵工具，其病因与转化生长因子？信号的失调有关。

 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.