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The potential role of hyaluronan in fertility regulation

Drs. Marie-Paule Van Damme and Tracey Brown,
Department of Biochemistry and Molecular Biology, Monash University

Dr. Lois Salamonsen,
Prince Henry's Institute for Medical Research

The aim of this project is to determine the possible role of HA in the preparation of the human endometrium (the lining of the uterus) for embryo implantation, a critical step in the establishment of pregnancy.

The endometrium is normally a hostile environment for embryo implantation however, for a few days in each menstrual cycle it attains a unique state of receptivity when if conception has occurred, the embryo will implant and the pregnancy will be established. Little is known of the molecular events which lead to the attainment of receptivity or how these events are disrupted in women in whom failure of implantation has been identified as the underlying reason for infertility.

During the menstrual cycle, the human endometrium undergoes extensive remodelling which is orchestrated by the ovarian steroid hormones. Reorganisation includes phases of cellular proliferation, differentiation and tissue breakdown along with alterations in the composition of the extracellular matrix. One of the components of the extracellular matrix, hyaluronan (HA), has been proposed to play an important role in a number of such biological processes. It provides a provisional matrix for supporting cellular migration, adherence and proliferation. Indeed, a correlation between HA expression and cell proliferation has been noted in a wide variety of different cell types. Importantly in the current context, HA increases suddenly on the day of implantation in the mouse uterus and appears to be associated with regions that contain stromal cells proliferating in preparation for embryo implantation.

HA is also responsible for the hydration and expansion of tissues due to its high content of negatively charged groups that attract a large associated volume of water. In the human endometrium, hydration occurs in two phases, the first during the mid-preovulatory phase associated with rapid cell proliferation and the second in the mid-postovulatory phase when embryo implantation would occur in a conception cycle. Studies from our laboratories have demonstrated that in humans, these two hydration phases correlate with two peaks of HA.

These data thus strongly support a role for HA in the preparation of the endometrium for embryo implantation, however nothing is known about how the peaks of HA in the endometrium are regulated although both synthetic (HA synthase) and degradative (hyaluronidase) enzymes have now been identified in other tissues.

The aims of this project will be to determine for both HA synthetic and degradative enzymes:

  1. The various forms of enzymes expressed in human endometrium at different phases of the cycle.
  2. The "relative" amounts of mRNA for each enzyme and their relationship to the varying content of HA during the cycle.
  3. The cellular location of mRNA for each enzyme expressed in the tissue.

These studies will be performed using basic Molecular Biology techniques such as Northern analyses, to determine the forms of HA synthases and hyaluronidases expressed in endometrium across the menstrual cycle and In situ hybridization to establish the cellular location of the enzymes.