Aging is universal and underlies chronic disease as well as tissue and cellular deterioration. The female reproductive system is the first to age in humans, with functional loss occurring decades prior to other organs. Reproductive aging is associated with both a decline in the number of eggs within the ovary and a decrease in their quality, which together, contribute to increased incidences of miscarriages, infertility, and birth defects. Our long-term objective is to attenuate the negative consequences of female reproductive aging, which are becoming more prevalent as women globally are delaying childbearing. Reproductive transitions, such as reproductive aging, is a priority of the Fertility and Infertility branch of the National Institutes of Health, and thus our work is tightly aligned with the mission of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Although considerable research has focused on age-associated changes in the egg, correspondingly less is known about how the ovarian stroma, the microenvironment in which the egg develops, changes with age and influences egg quality. A key stromal molecule found in the ovaries is hyaluronan. Hyaluronan is synthesized and fragmented in inflamed tissues and provides signals that exacerbate inflammation and drive fibrosis in several organs. Changes in hyaluronan are also implicated in aging tissues. Here, we will test the overarching hypothesis that ovarian hyaluronan levels decrease with age along with a corresponding increase in fragmentation of existing HA into a population of small molecules central to the pathogenesis of ovarian fibrosis and inflammation, which impacts egg quality. This hypothesis will be tested in three specific aims. First, we will examine how hyaluronan content, fragmentation, and function change in the ovary with advanced reproductive age. These studies will be performed using reproductively young and reproductively old mice and will include analysis of ovarian biomechanical properties and the impact of hyaluronan fragmentation on ovarian follicle development. Second, we will investigate the extent to which perturbation of hyaluronan expression in vivo induces ovarian stromal inflammation and fibrosis. To accomplish this goal, we will evaluate indices of inflammation and fibrosis in mice genetically or pharmacologically deficient in hyaluronan and correlate this with fertility. Third, we will determine how human ovarian and follicular fluid hyaluronan levels and fragmentation profiles change with age using human material provided by two established research repositories at Northwestern University. We will investigate the clinical relevance of our findings by correlating hyaluronan levels and fragmentation profiles with reproductive aging markers and pregnancy outcomes after assisted reproductive technologies. The premise that the ovarian stroma contributes to reproductive aging represents a novel research frontier. Completion of the studies outlined in this proposal may reveal novel hyaluronan-related therapeutic targets or points of intervention aimed at improving fertility.
The female reproductive system ages decades prior to other organs and results in infertility, miscarriages, and birth defects - with such adverse consequences of particular concern as women worldwide are delaying childbearing. We recently identified fibrosis and inflammation as a hallmark of the aging ovarian microenvironment in which eggs grow and develop, and in this proposal we seek to investigate the underlying mechanism to ultimately counteract this phenomenon and improve reproductive longevity and outcomes. We will test the hypothesis that age-associated loss and fragmentation of a key extracellular matrix molecule (hyaluronan) in the mammalian ovary converts the normally homeostatic microenvironment into a reactive matrix that drives fibrosis and inflammation.