Succesful implantation requires a receptive uterine endometrium. Any flaws in uterine endometrial receptivitycan lead to implantation defects or failure. Currently, we have no clear answers for how the uterineendometrium achieves its receptivity, or how endometrial receptivity can be predicted or controlled. In thisregard, the discovery of endometrial receptivity and non-receptivity markers offers a great promise.Implantation in primiparous or multiparous rodents only occurs in between two nodular (inter-nodular) areas,but not at nodular areas created at placental ejection sites after the end of pregnancy. This uterine region-based implantation strategy in parous mice could be due to loss of endometrial receptivity at the nodular, butnot at the inter-nodular endometrium. These two dissimilar functional regions of the same uterine horn ofparous mice offer an entirely new approach to discover morphological criteria and/or molecules pivotal toinduce uterine nonreceptivity and/or receptivity. Thus, the goal of this application is to 1) demonstratewhether uterine receptive and non-receptive states can be discerned by morphological criteria of uterineluminal epithelial cells and/or vascular architecture, and 2) identify the molecule(s) whose upregulation ordownregulation and/or no expression makes the uterine nodular sites, but not the inter-nodular sites,unsuitable for blastocyst implantation. Our working hypothesis is that morphological criteria and/or genesthat are unique to either nodular or inter-nodular areas on day 4 of pregnancy could serve as excellentindicators for either poor or optimal uterine receptivity, respectively.
Two Specific Aims will be pursuedin primiparous (Para 1) mice on day 4 (the day of uterine receptivity) of their 2nd pregnancy to fulfill our goal.
Specific Aim 1 will assess luminal epithelial surface morphology and blood vessels distributionchanges at the nodular and inter-nodular uterine areas.
Specific Aim 2 will discover molecule(s)responsible for uterine receptivity and/or non-receptivity by comparing genomic profiles of uterinetissues or cells from the nodular and inter-nodular areas over a period of time when uterine transitionfrom the non-receptive state to the receptive state occurs. We will use multiple experimental approachesincluding scanning electron microscopy, laser captured microscopy, corrossion casting, punch biopsy, RNA-Sequencing, quantitative PCR, in situ hybridization, and immunohistochemistry to acomplish our goals.The outcome of our studies will provide useful information for the development of diagnostic and therapeutictools that can be used for detection, prevention and treatment of female reproductive disorders, and improvetechnologies for assisted reproduction and contraception.
We propose here an exclusively new animal (primiparous mouse) model in order to identify the uterinemolecule(s) required for inducing uterine receptivity and/or nonreceptivity for implantation. The outcome of ourstudies will potentially aid in women's reproductive health related issues such as: 1) the causes and therapy forunexplained infertility; and pregnancy loss; 2) better understanding of normal and abnormal implantation andpregnancy; 3) improve pregnancy outcome by reducing the incidence of recurrent ART failure; and 4)development of a new generation post-coital contraceptive by modulating uterine receptivity and implantation.
| Robuck, Michael F; O'Brien, Christine M; Knapp, Kelsi M et al. (2018) Monitoring uterine contractility in mice using a transcervical intrauterine pressure catheter. Reproduction 155:447-456 |
| Jones-Paris, Celestial R; Paria, Sayan; Berg, Taloa et al. (2017) Embryo implantation triggers dynamic spatiotemporal expression of the basement membrane toolkit during uterine reprogramming. Matrix Biol 57-58:347-365 |
| Herington, Jennifer L; Guo, Yan; Reese, Jeff et al. (2016) Gene profiling the window of implantation: Microarray analyses from human and rodent models. J Reprod Health Med 2:S19-S25 |
