TGF-BETA Signaling in Endometrial Cell Function and Dysfunction
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Title:TGF-BETA SIGNALING IN ENDOMETRIAL CELL FUNCTION AND DYSFUNCTIONProject Summary/An increasing number of reproductive-aged women face pregnancy loss and infertility, some of which isassociated with endometrial dysfunction. A lack of understanding of mechanisms governing endometrialdevelopment and function prevents an effective treatment for such disorders. Therefore, there is a criticalneed to define the mechanisms underlying endometrial cell proliferation, differentiation, and function.Research on human endometrial function during pregnancy remains challenging due to ethical constrains onthe access to tissue specimens, making the mouse model particularly valuable. Transforming growth factor β(TGFβ) superfamily signaling regulates fundamental cellular functions and developmental processes inreproductive organs including the uterus. The in vivo function of TGFβ signaling in uterine biology remainspoorly understood due to the redundancy of TGFβ ligands and lack of appropriate animal models. Bygenetically manipulating TGFβ type 1 receptor (TGFBR1) using both loss-of-function and gain-of-functionmouse models, we have discovered that TGFβ signaling is required for fertility and female reproductive tractdevelopment. Guided by our compelling preliminary findings, the overall objective in this R01 proposal is todecipher the cellular, molecular, and epigenetic mechanisms underpinning endometrial cell proliferation,differentiation, and function. Our central hypothesis is that endometrial cell properties and function areregulated by a well-balanced TGFβ signaling system essential for uterine development and pregnancy. Wewill test our hypothesis by pursuing the following two specific aims: 1) Define how TGFβ signaling regulatesendometrial epithelial cell proliferation during uterine development. 2) Identify the role and associatedmechanism of TGFβ signaling in endometrial stromal cell function and dysfunction during pregnancy. Theproposed research is innovative because it involves the use of unique and complementary novel mousemodels to decipher the role and associated mechanisms of TGFβ signaling in endometrial cells, theapplication of uterine epithelial and stromal cell culture and co-culture system to uncover howTGFβ signaling regulates stromal-epithelial interaction, a key but poorly defined event in uterine developmentand function, and the identification of TGFBR1-dependent epigenetic mechanisms in endometrial stromalcells. Studies proposed in this application represent the next step in a continuum of research toward thedevelopment of targeted interventions for endometrial dysfunction and pregnancy complications. Thus,completion of this proposal is expected to provide a new paradigm for understanding the mechanisms ofendometrial dysfunction, and provide a rational basis for future research that focuses on testing thetranslational potential of targeting TGFβ signaling cascade in the treatment of endometrial dysfunction.
