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TGF-BETA SIGNALING IN ENDOMETRIAL CELL FUNCTION AND DYSFUNCTION

子宫内膜细胞功能和功能障碍中的 TGF-β 信号传导

基本信息

批准号：
10112273
负责人：
Qinglei Li
金额：
$ 29.77万
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：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112273
关键词：
Animal Model Apoptosis Biology Cell Communication Cell Culture Techniques Cell Differentiation process Cell Proliferation Cell physiology Cells Clinical Coculture Techniques Complement Factor B Data Decidua Decidual Cell Reactions Development Developmental Process Diagnostic Disease Endocrine Endometrial Endometrial Stromal Cell Ensure Epigenetic Process Epithelial Cell Proliferation Epithelial Cells Epithelial-Stromal Communication Ethics Event Face Female Fertility Foundations Functional disorder Goals Growth Factor Human Impairment Infertility Intervention Knowledge Ligands Literature Mesenchymal Mission Molecular Molecular Genetics Mus National Institute of Child Health and Human Development Pathologic Physiological Play Pregnancy Pregnancy Complications Pregnancy Outcome Pregnancy loss Production Property Regulation Reproduction Reproductive Process Research Role Signal Transduction Specimen Stromal Cells System TGFBR1 gene Testing Therapeutic Intervention Tissues Transforming Growth Factor beta Transforming Growth Factors Uterine Diseases Uterus Woman aged base conditional knockout design effective therapy expectation gain of function genetic manipulation improved in vivo innovation loss of function member mouse model novel novel therapeutics paracrine prevent prophylactic receptor reproductive reproductive organ reproductive tract treatment strategy

项目摘要

Title: TGF-BETA SIGNALING IN ENDOMETRIAL CELL FUNCTION AND DYSFUNCTION Project Summary/Abstract An increasing number of reproductive-aged women face pregnancy loss and infertility, some of which is associated with endometrial dysfunction. A lack of understanding of mechanisms governing endometrial development and function prevents an effective treatment for such disorders. Therefore, there is a critical need to define the mechanisms underlying endometrial cell proliferation, differentiation, and function. Research on human endometrial function during pregnancy remains challenging due to ethical constrains on the access to tissue specimens, making the mouse model particularly valuable. Transforming growth factor β (TGFβ) superfamily signaling regulates fundamental cellular functions and developmental processes in reproductive organs including the uterus. The in vivo function of TGFβ signaling in uterine biology remains poorly understood due to the redundancy of TGFβ ligands and lack of appropriate animal models. By genetically manipulating TGFβ type 1 receptor (TGFBR1) using both loss-of-function and gain-of-function mouse models, we have discovered that TGFβ signaling is required for fertility and female reproductive tract development. Guided by our compelling preliminary findings, the overall objective in this R01 proposal is to decipher the cellular, molecular, and epigenetic mechanisms underpinning endometrial cell proliferation, differentiation, and function. Our central hypothesis is that endometrial cell properties and function are regulated by a well-balanced TGFβ signaling system essential for uterine development and pregnancy. We will test our hypothesis by pursuing the following two specific aims: 1) Define how TGFβ signaling regulates endometrial epithelial cell proliferation during uterine development. 2) Identify the role and associated mechanism of TGFβ signaling in endometrial stromal cell function and dysfunction during pregnancy. The proposed research is innovative because it involves the use of unique and complementary novel mouse models to decipher the role and associated mechanisms of TGFβ signaling in endometrial cells, the application of uterine epithelial and stromal cell culture and co-culture system to uncover how TGFβ signaling regulates stromal-epithelial interaction, a key but poorly defined event in uterine development and function, and the identification of TGFBR1-dependent epigenetic mechanisms in endometrial stromal cells. Studies proposed in this application represent the next step in a continuum of research toward the development 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 of endometrial dysfunction, and provide a rational basis for future research that focuses on testing the translational potential of targeting TGFβ signaling cascade in the treatment of endometrial dysfunction.