The fundamental role of transforming growth factor (TGF) superfamily signaling in reproduction has been witnessed over the past two decades. Despite enormous research efforts, the definitive role of TGF signaling in the ovary remains unknown. Notably, over activation of TGF 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 TGF 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 TGF 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 #1 a): Define the effect of over activation of TGFBR1 on follicular development, hormone profiles, and ovarian response to hormones.
Specific Aim #1 b): Identify molecular mechanisms underpinning TGF 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 TGF signaling in promoting ovarian granulosa cell proliferation, highlighting the unique function of TGF 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 TGF signaling.
Our proposed studies to identify TGF targets in the ovary are relevant to the mission of NICHD because TGF signaling is fundamental for female reproduction. Precisely controlled proliferation of ovarian granulosa cells is critical for follicuar development, ovulation, and fertility. Therefore, identification of novel genes and pathways regulating granulosa cell proliferation/differentiation using our unique mouse model will aid in the design of new treatment strategy for female reproductive diseases associated with dysregulated TGF signaling.
| Fang, Xin; Ni, Nan; Gao, Yang et al. (2018) A novel mouse model of testicular granulosa cell tumors. Mol Hum Reprod 24:343-356 |
| Ni, Nan; Gao, Yang; Fang, Xin et al. (2018) Glandular defects in the mouse uterus with sustained activation of TGF-beta signaling is associated with altered differentiation of endometrial stromal cells and formation of stromal compartment. PLoS One 13:e0209417 |
| Gao, Yang; Vincent, David F; Davis, Anna Jane et al. (2016) Constitutively active transforming growth factor ? receptor 1 in the mouse ovary promotes tumorigenesis. Oncotarget 7:40904-40918 |
| Fang, Xin; Gao, Yang; Li, Qinglei (2016) SMAD3 Activation: A Converging Point of Dysregulated TGF-Beta Superfamily Signaling and Genetic Aberrations in Granulosa Cell Tumor Development? Biol Reprod 95:105 |
