Homeostatic to reactive hyaluronan matrices in ovarian reproductive aging

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, an extracellular matrix glycosaminoglycan. 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 into a population of small molecules central to the pathogenesis of ovarian fibrosis and inflammation, which impact 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