Decidualization is an absolutely essential process for the successful establishment of pregnancy in primates and rodents. The decidual process is associated with a morphological transformation of fibroblast cells to highly secretory epitheloid-like cells coupled with a biochemical reprogramming of the endometrial stromal cells. As a consequence of this differentiation process, decidualized stromal cells acquire the unique ability to regulate trophoblast invasion, resist inflammatory and oxidative insults and dampen local maternal immune responses. However, the early events that permit these cells to initiate their differentiation cascade have yet to be elucidated. The understanding of these mechanisms are critical since impaired decidualization is associated with numerous gynecological malignancies in women with a broad range of etiologies from infertility to early pregnancy loss. During the previous funding period we demonstrated that the early primate embryonic signal, chorionic gonadotropin (CG), coupled with progesterone, directly modulates endometrial gene expression and alters the cytoskeletal architecture of uterine stromal fibroblasts. These cytoskeletal changes are necessary to prevent the stromal cells from undergoing apoptosis in a conceptual cycle and allow for cellular restructuring during decidual transformation. Our data also demonstrated for the first time that the evolutionary conserved Notch1 protein, which plays a critical role in cell fate decisions, is regulated by CG and progesterone in endometrial stromal cells in vivo and in vitro. The importance of Notch1 in the decidualization process was evident in a genetically modified mouse model that failed to decidualize when Notch1 was specifically ablated in the uterus. Based on these studies three specific aims are proposed in this application to elucidate the role of Notch1 in inhibiting stromal cell apoptosis and initiating the decidualization process.
In Specific Aim 1 we will test the hypothesis that the induction and activation of Notch1 by CG and progesterone is required to induce -smooth muscle actin (SMA) in uterine stromal fibroblasts. The proposed studies will focus on the transcriptional regulation of SMA expression by Notch1 in stromal fibroblasts and whether this in turn prevents the cells from undergoing apoptosis.
Specific Aim 2 will test the hypothesis that the Notch1 mediated decrease in FOXO3a and Notch1 mediated increase in IL-11 is a necessary prerequisite for the initiation of decidualization. FOXO3a is suppressed during decidualization and another Notch1 targert, IL-11, is an earlier initiator of the decidualization process. Studies proposed in these two aims will utilize human uterine fibroblast cells (HuF cells).
In Specific Aim 3 we will use the PRCre/+Notch1flox/flox bigenic mouse mouse that we have generated. This model demonstrates a significant decidualization failure and provides an in vivo model to identify the molecular and cellular targets of Notch1 that are required for the decidualization response. It is anticipated that these studies will provide critical information on the decidualization process and translate to therapeutic potentials of Notch1 for women with decidual defects. We believe a better understanding of the molecular mechanisms responsible for decidualization and implantation will improve clinician's ability to detect, diagnose and treat early pregnancy loss.

Public Health Relevance

Understating the mechanisms that govern decidualization is critical to the successful establishment of pregnancy. Several disease conditions such as endometriosis and endometrial cancer are associated with impaired decidualization. The proposal studies will focus on the role of Notch 1 in stromal cell differentiation. Although implicated in the developmental regulation of cell fate and multiple malignancies its physiological role in uterine biology has never been studied. Thus, given its current clinical potential these studies may provide insight into new therapeutic targets for decidualization failure.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD042280-09
Application #
8444526
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Yoshinaga, Koji
Project Start
2002-02-01
Project End
2014-09-30
Budget Start
2013-04-01
Budget End
2014-09-30
Support Year
9
Fiscal Year
2013
Total Cost
$284,468
Indirect Cost
$97,318
Name
Michigan State University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Su, Ren-Wei; Strug, Michael R; Jeong, Jae-Wook et al. (2016) Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility. Proc Natl Acad Sci U S A 113:2300-5
Su, Ren-Wei; Fazleabas, Asgerally T (2015) Implantation and Establishment of Pregnancy in Human and Nonhuman Primates. Adv Anat Embryol Cell Biol 216:189-213
PrabhuDas, Mercy; Bonney, Elizabeth; Caron, Kathleen et al. (2015) Immune mechanisms at the maternal-fetal interface: perspectives and challenges. Nat Immunol 16:328-34
Devi, Y Sangeeta; DeVine, Majesta; DeKuiper, Justin et al. (2015) Inhibition of IL-6 signaling pathway by curcumin in uterine decidual cells. PLoS One 10:e0125627
Su, Ren-Wei; Strug, Michael R; Joshi, Niraj R et al. (2015) Decreased Notch pathway signaling in the endometrium of women with endometriosis impairs decidualization. J Clin Endocrinol Metab 100:E433-42
Yoshinaga, Koji; PrabhuDas, Mercy; Davies, Christopher et al. (2014) Interdisciplinary collaborative team for blastocyst implantation research: inception and perspectives. Am J Reprod Immunol 71:1-11
Geisert, Rodney; Fazleabas, Asgerally; Lucy, Mathew et al. (2012) Interaction of the conceptus and endometrium to establish pregnancy in mammals: role of interleukin 1ýý. Cell Tissue Res 349:825-38
Afshar, Yalda; Miele, Lucio; Fazleabas, Asgerally T (2012) Notch1 is regulated by chorionic gonadotropin and progesterone in endometrial stromal cells and modulates decidualization in primates. Endocrinology 153:2884-96
Afshar, Yalda; Jeong, Jae-Wook; Roqueiro, Damian et al. (2012) Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse. FASEB J 26:282-94
Banerjee, Prajna; Fazleabas, Asgerally T (2011) Extragonadal actions of chorionic gonadotropin. Rev Endocr Metab Disord 12:323-32

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