Early pregnancy loss affects roughly 15% of known pregnancies and may be even more common in obese women. A prominent cause of early pregnancy loss is failure of implantation, which requires that the uterine endometrial stromal cells undergo decidualization. Additionally, recent work has revealed an important role for metabolic regulation in in this process. Specifically, the decidualizing stromal cells produced less ATP and more NADPH and ribose-5-phosphate via the pentose phosphate pathway, which is used to produce nucleotides. Thus this event occurs at the expense of reduced glycolysis; how these cells compensate for this decrease in energy production is unknown. This gap in knowledge limits our ability to discover new therapeutic strategies to improve pregnancy outcomes. Our long-term goal is to understand the metabolic and molecular mechanisms responsible for endometrial stromal cell decidualization so that effective therapies for improving this process can be developed and used to prevent early pregnancy loss, especially in the increasing population of obese women. Here, we will test the central hypothesis that initiation of the cellular recycling pathway autophagy plays a key role in decidualization in both humans and mice. We will test our hypothesis by pursuing the following specific aims:
Aim 1. Determine the role of autophagy in decidualization. Our working hypothesis is that decidualization depends on induction of autophagy both in vitro and in vivo. We will determine the effect of genetic or pharmacologic block of autophagy on decidualization of both mouse and human endometrial stromal cells. We will assess the effect of autophagy inhibition on both artificial and pregnancy-induced decidualization in a genetic knock out mouse model deficient in two different autophagic genes, Atg16L1 and Beclin1, allowing us to assay not only decidualization, but also embryo implantation and pregnancy outcomes.
Aim 2. Define the function of GLUT8 in decidualization. We will test the hypothesis that the impaired decidualization and subfertility of Glut8 knockout mice are due to a loss of autophagy in endometrial stromal cells. We will address this by measuring autophagy in Glut8-null endometrial stromal cells and asking whether the defects can be reversed by inducing autophagy. We will also determine whether inducing autophagy can improve pregnancy rates in Glut8 knockout mice.
Aim 3 : Determine the mechanism by which saturated fatty acids impair decidualization. We will test our hypothesis that saturated free fatty acids inhibit autophagy by examining steps in autophagy and the signaling pathway that activates autophagy. We will also perform in vitro and in vivo mouse and human experiments to assess the ability of activators of autophagy to reverse the deleterious effects of high-fat diet, saturated fatty acids, and obesity on decidualization and reproductive outcomes. U[on completion of these aims we expected the following outcomes: 1) demonstration that autophagy is essential to optimal decidualization, and thus, implantation; 2) determination of the role of GLUT8 in decidualization; and 3) explanation of how diet can influence decidualization and implantation. This work will have an important impact on the fertility field by revealing mechanisms that are critical to successful decidualization, implantation, and overall pregnancy outcomes. This work will provide support for establishment of dietary guidelines and development of new therapeutics, such as autophagic activators, to possibly move into clinical trials to treat women with impaired implantation and pregnancy loss.
Early pregnancy loss is the most common complication of human pregnancy. Studies have estimated that 30% of embryos undergo demise before implantation (preimplantation loss) and another 30% are lost before six weeks of pregnancy (preclinical or biochemical loss). Although much is known of the process of implantation, requiring a receptive epithelial layer of the uterine lining and the extra-embryonic cells (trophoblasts) of a competent embryo, little is known of the underlying stromal cells and their decidualization, the essential differentiation process by which these underlying cells become receptive to implantation. This work will have an important impact on the fertility field by revealing mechanisms that are critical to successful decidualization, implantation, and overall pregnancy outcomes.
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