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- Title
- THE ROLE OF ARID1A IN ENDOMETRIOSIS-RELATED INFERTILITY
- Creator
- Marquardt, Ryan Michael
- Date
- 2022
- Collection
- Electronic Theses & Dissertations
- Description
-
The inner lining of the uterus, the endometrium, is composed of a luminal epithelial cell layer supported by an underlying stroma which contains epithelial gland structures. These distinct cell types coordinate with complex and dynamic molecular crosstalk tightly controlled by ovarian steroid hormones to regulate a healthy menstrual cycle and support the initiation and maintenance of a healthy pregnancy. Endometriosis occurs when endometrium-like tissue forms lesions outside the uterine...
Show moreThe inner lining of the uterus, the endometrium, is composed of a luminal epithelial cell layer supported by an underlying stroma which contains epithelial gland structures. These distinct cell types coordinate with complex and dynamic molecular crosstalk tightly controlled by ovarian steroid hormones to regulate a healthy menstrual cycle and support the initiation and maintenance of a healthy pregnancy. Endometriosis occurs when endometrium-like tissue forms lesions outside the uterine cavity, and this painful disease afflicts about 10% of reproductive-age women, an estimated 176 million worldwide. Up to 50% of these individuals also experience infertility, and many cases cannot be explained by morphological or ovarian defects, which implicates a uterine environment that is non-receptive to embryo implantation. The molecular basis for the correlation between endometriotic lesion presence and a non-receptive endometrium is unclear, but available evidence suggests that dysregulation of epigenetic regulators may play a role. Expression of AT-rich interaction domain 1A (ARID1A), a chromatin remodeling factor, is lost in some endometriotic lesions and markedly reduced in endometrial biopsies from infertile women with endometriosis, but it is essential in the uterus for fertility. This dissertation evaluates the overarching hypothesis that ARID1A loss connects endometriosis and infertility by causing increased lesion development and a non-receptive endometrium. Chapter 1 provides a review of the current literature on the topics of normal ovarian steroid hormone regulation of endometrial function, the dysregulation that occurs in endometriosis with its clinical implications and therapeutic options, and the specific involvement of ARID1A in endometrial pathophysiology. Chapter 2 delineates a critical role for endometrial epithelial ARID1A in uterine gland function for fertility. Chapter 3 reports the need for endometrial epithelial ARID1A to maintain uterine immune homeostasis during early pregnancy. Chapter 4 explores the involvement of endometrial ARID1A loss in a mouse model of endometriosis-related infertility. Chapter 5 describes a method for in vivo photoacoustic imaging of this endometriosis mouse model through the application of nanoparticle labeling. Finally, Chapter 6 summarizes the findings, discusses conclusions from the synthesized data in the context of the current literature, and provides ideas for future studies of related topics. Together, the studies herein make the case that endometrial ARID1A loss contributes to endometriosis-related infertility by exacerbating endometriotic lesion formation and compromising the ability of the endometrium to maintain the gland function and immune homeostasis necessary for the establishment and maintenance of pregnancy. Continued investigation through studies like these is key to understanding endometrial pathophysiology at the molecular level in order to enable development of targeted treatment options for women suffering the devastating effects of endometriosis and related infertility.
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