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The peri-implantation period in mammals is critical with respect to survival of the conceptus and establishment of pregnancy. During this period of pregnancy, reciprocal communication between ovary, conceptus, and endometrium is required for successful implantation and placentation. Therefore, studies were conducted to indentify and characterize novel endometrial genes important for implantation and conceptus development in the ovine uterus. The first and second studies defined the uterine expression of seven members of the cathepsin (CTS) family of lysosomal proteases, and a secreted inhibitor of CTSL called cystatin C (CST3) during the peri-implantation period. In addition, regulation of CTS and CST3 by progesterone (P4) and interferon tau (IFNT) was evaluated. CTSL was the most abundant CTS in the ovine ovine uterus and was also coordinately expressed with CST3 in the endometrial epithelia and conceptus trophectoderm. CTSL and CST3 were found to be novel P4-induced and IFNT-stimulated genes in the luminal epithelial cells of the ovine endometrium. The third study identified radical S-adenosyl methionine domain containing 2 (RSAD2) and interferon-induced with helicase C domain 1 (IFIH1) in the ovine uterus. Results of this study indicated that IFNT induces RSAD2 and IFIH1 in a P4-independent manner in the stroma, immune cells, and glands of the ovine endometrium. These two genes are proposed to have biological roles in the establishment of uterine receptivity to the conceptus during implantation. The fourth study characterized endometrial expression of stanniocalcins (STC) during pregnancy. STC1 appeared in the endometrial glands on Day 18 of pregnancy, increased from Days 18 to 80, and remained abundant through Day 120 of gestation. In addition, this study demonstrated that STC1 is induced by P4 and increased by placental hormones, such as placental lactogen (CSH1) and growth hormone (GH), in the ovine endometrial glands. Collectively, these studies identified genes that are expected to be critical to unraveling the mechanism(s) of reciprocal fetal-maternal interactions required for successful implantation and pregnancy. A more complete understanding of these genes will be important for developing therapeutic strategies to prevent, treat and/or diagnose infertility in domestic animals and humans, because they are biomarkers of P4 and/or IFN effects.

xiii, 159 leaves : tables ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Human Physiology and Pharmacology, 1980

Thesis (M.S.)--Villanova University, 2008. / Biology Dept. Includes bibliographical references.

Thesis (Ph.D.)--University of Delaware, 2006. / Principal faculty advisor: Daniel D. Carson, Dept. of Biological Sciences. Includes bibliographical references.

Thesis (Ph. D.)--University of Idaho, 2005. / Also available online in PDF format. Abstract. "December 2005." Includes bibliographical references.

Proefschrift Maastricht. / Met lit.opg.

Decidualization involves the differentiation of the endometrial tissue into the decidual tissue of the pregnant uterus in several species including humans and rodents. This differentiation occurs only after the onset of implantation in mice and can be artificially-induced causing the formation of deciduomal tissue. The purpose of this study was to identify a group of differentially expressed genes between the developing decidua and deciduoma and study their expression as it may relate to conceptus influenced changes in endometrial gene expression during decidualization. In this study we artificially induced decidualization by transferring blastocyst-sized ConA-coated agarose beads into the uterus on Day 2.5 of pregnancy as we had previously found this model to be more "physiological". Total RNA was isolated from implantation sites of the uteri of pregnant mice as well as pseudopregnant mice that received beads. This RNA was then used for microarray analysis using Mouse Illumina Beadarray chips. This revealed potential differential mRNA levels of over 1,000 genes between the decidua and bead-induced deciduoma tissues of Day 7.5 pregnant and pseudopregnant mice, respectively. Of these, the mRNA levels of 102 genes were 2-fold greater in the decidual tissue while almost twice as many were 2-fold greater in the deciduoma. The broad functions of the protein encoded by the mRNAs included protein binding (e.g. Copz1, Gjb2, Dctn1, Islr, Nisch, Wwc1, Cdc20, Rxrb, Klhl7, Adam10), calcium transport (e.g. Anxa6, Itga11, Clta, Smoc2, Vdr), hydrolase/peptidase activity (e.g. Klk5, Klk26, Klk24, Tmprss4, Ptpn14, Ddx3x, Atp1a2, Usp25, Smarca1), ligase activity (e.g. Iars, Farsla, Ube2v1, Cbll1, Rnf19, Mccc1), and transcription (e.g. Irf1, Hip1, Bhlha15, Supt6h, Scand1, Myocd, Sp3, Mitf, Papolg). We confirmed the differential mRNA levels of a number of gene transcripts using quantitative RT-PCR. Finally, the level and localization of some of the mRNA's identified by our microaray analysis were examined in the mouse uterus during decidualization in more detail and included: Aldh3a1, Bcmo1, Guca2b, GCC, and Inhbb. Localization of mRNA expression in the Day 7.5 implantation site occurred in the mesometrial region near the lumen (Aldh3a1), luminal and glandular epithelia (Guca2b), and endothelial cells lining the sinusoids (Inhbb). This study provides the identity and expression analysis of steady-state mRNA levels of genes whose expression may be influenced by the conceptus using a physiological model for implantation.

Bacterial contamination of the female genital tract after parturition is common and subsequent infections are associated with infertility. Infections of the uterus or mammary gland in cattle perturb ovarian function, with decreased dominant follicle growth rate and delayed ovulation. Granulosa cells that line ovarian follicles express the molecular machinery necessary to respond to common bacterial pathogen-associated molecular patterns (PAMPs), suggesting that granulosa cells may play a role in ovarian innate immunity. In the present thesis, the effect of bacterial PAMPs on ovarian follicle cells was examined during follicular growth, from emergence through dominance, and the early stages of embryogenesis. Granulosa cells from emerged or dominant bovine follicles increased production of inflammatory mediators, such as IL-6 and IL-8, through Toll-like receptor (TLR)-dependent pathways in response to the PAMPs lipopolysaccharide and the synthetic triacylated lipopeptide Pam3CSK4. The requirement for TLR2 and TLR4 was confirmed by using siRNA, showing activation of MAPK intracellular pathways and inhibiting key signals (p38, MEK or NFkB) in TLR pathways. The endocrine function of granulosa cells was perturbed by PAMPs, with decreased oestradiol and progesterone output. In addition, the endocrine environment affected granulosa cellular responses, with high EGF increasing the cellular response to PAMPs. Bacterial PAMPs also perturbed the oocyte, with increased cumulus expansion and parthenote cleavage rate, as well as changes in key genes involved in oocyte maturation. Finally, a human granulosa cell line was used to examine if PAMPs perturb human as well as bovine ovarian health. Indeed, human cells also expressed TLRs and mounted a cellular response to PAMPs at the mRNA level. This thesis provides a molecular mechanism for the perturbation of ovarian function by an infection at a site distal to the ovary.

Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / The action of progesterone and estrogen on uterine mast cells of the ovariectomized rat was studied. A single injection of estradiol-17B (0.25 μg) produced a highly significant (P < O.OO1) reduction in both mesometrial and antimesometrial mast cell populations. The mean ± S.E. number of mesometrial and antimesometrial mast cells in the control animals was 19.2 ± 1.3 and 6.3 ± 0.7 respectively, while in the estrogen treated animals the respective values at 15 hours post treatment were 4.1 ± 0.5 and 2.9 ± 0.4. Estrogen treatment also resulted in considerable degranulation of the mast cells. In comparison, progesterone, when administered as a single injection (5 mg) did not produce a drastic reduction of the mast cells. Fifteen hours after its administration, progesterone had produced only a moderate reduction of the mast cell population; however, the decline was significantly smaller than those values obtained at the same time interval following estrogen treatment. Since it is known that progesterone treatment for at least 48 hours, followed by estrogen constitute the basic hormonal sequence for decidualizationin the rat, experiments were designed to study possible relationship between mast cell population and deciduoma development. Results obtained from these experiments demonstrate quite clearly that maximal decidual response was possible only among animals treated over a 48 hour period with progesterone (5 mg/ 24 hours) followed by a small (0.25 μg) injection of estradiol-17B and then traumatized 15 hours later (at a time when mast cell population was reduced to the lowest level). Thus, the hormonal treatment which resulted in the lowest level of mast cell numbers also permitted the largest deciduoma development. Shelesnyak (1957) proposed that histamine play a vital role in decidualization in the rat. On the other hand, it has been shown that mast cell degranulation with the accompanying loss of metachromasia is related to histamine release (Thon, 1967). In order to evaluate the role of estrogen as opposed to that of histamine in decidualization, animals were treated with estrogen and progesterone in addition to an estrogen antagonist -CN-55,945-27. The data from these experiments indicated only a moderate decidual response among the treated animals. In addition, the mast cell population in the uterine wall of these animals, at the time of traumatization, was considerably reduced and degranulated. Thus, uninterrupted estrogen action seems to be necessary for the establishment of sensitivity for maximal deciduoma development. In another set of investigations, uterine mast cells were depleted by administration of compound 48/80. Animals depleted of their mast cells and then treated with progesterone, estrogen, followed by trauma developed only small to moderate deciduomata. However, when rats were allowed to recover for seven days (at which time over 50% of the mast cells had reappeared) and then given the treatment as the preceding group, massive full length deciduoma were produced. The evidence suggests that maximal uterine sensitivity to decidualization is possible only after adequate hormonal treatment, and only in uteri not depleted of mast cells. / 2031-01-01