The myometrium plays a fundamental role in a variety of female reproductive events and has a significant impact on pregnancy outcome. The structural and functional abnormalities of myometrium can lead to reproductive disorders, such as implantation failure, preterm labor, and uterine rupture, some of which are severe causes of neonatal mortality and morbidity. Despite the long-recognized importance of myometrial function in pregnancy, key signaling pathways that control myometrial development and function are not well defined. Lack of this knowledge is partially due to the lack of an animal model with myometrial defects resulting from disruption of defined cell signaling pathways. This creates a significant barrier that prevents an effective therapeutic intervention for myometrial dysfunction. Our objective of this proposal is to define the role of transforming growth factor (TGF) signaling in myometrium, and identify the contribution of dysregulated TGF signaling to the development of uterine diseases. We hypothesize that TGF signaling is required for myometrial development and function, and dysregulated myometrial TGF signaling is linked to uterine diseases such as adenomyosis. We will test our hypothesis in two specific aims: 1) Identify the role of TGF signaling in myometrial contractility and pregnancy;and 2) Define the mechanistic contributions of dysregulated TGF signaling to the development of myometrial defects and uterine adenomyosis. To achieve these aims, we will use complementary approaches including a conditional knockout strategy and in vitro assays to test our working hypotheses. Successful completion of the proposed application will help to uncover the signaling pathways that control the structural and functional properties of the myometrium, and achieve a new paradigm for understanding the mechanisms underlying myometrial pathologies. These data could potentially guide the design of novel therapies for myometrial dysfunction and myometrium-associated diseases.

Public Health Relevance

Our proposal is relevant to the mission of NICHD because TGF signaling pathway is critical in regulation of female reproduction. The myometrium plays a fundamental role in a variety of female reproductive events and has a significant impact on pregnancy outcome. Therefore, uncovering the role of TGF signaling pathway in myometrial development and function will potentially lead to the discovery of novel diagnostic and therapeutic strategies for myometrial dysfunction and uterine diseases.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HD073756-01
Application #
8358471
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Yoshinaga, Koji
Project Start
2012-08-06
Project End
2014-07-31
Budget Start
2012-08-06
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$222,269
Indirect Cost
$67,410
Name
Texas Agrilife Research
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
847205713
City
College Station
State
TX
Country
United States
Zip Code
77843
Gao, Yang; Duran, Samantha; Lydon, John P et al. (2015) Constitutive activation of transforming growth factor Beta receptor 1 in the mouse uterus impairs uterine morphology and function. Biol Reprod 92:34
Li, Qinglei (2014) Transforming growth factor ? signaling in uterine development and function. J Anim Sci Biotechnol 5:52
Gao, Yang; Li, Shu; Li, Qinglei (2014) Uterine epithelial cell proliferation and endometrial hyperplasia: evidence from a mouse model. Mol Hum Reprod 20:776-86
Gao, Yang; Bayless, Kayla J; Li, Qinglei (2014) TGFBR1 is required for mouse myometrial development. Mol Endocrinol 28:380-94