[R01] Effects of the ovarian mechanical properties on folliculogenesis
Ente: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Scadenza: 2031-03-31
Importo max: 461.435 EUR
Paese: US
Descrizione
SUMMARY
Reproductive aging is associated with declines in follicle number, oocyte quality, and production of the ovarian
hormones estrogen and progesterone. The cessation of ovarian function at menopause is associated with
multiple pathologies, such as osteoporosis, because ovarian hormones regulate many tissues, resulting in an
acceleration of overall aging. One hallmark of ovarian aging in mice and humans is increased inflammation in
the ovarian stroma and follicles. However, the mechanisms driving follicle inflammation are not fully known,
hampering the development of novel treatment strategies to preserve female reproductive health. One common
outcome of inflammation is increased tissue stiffness, driven by remodeling of the extracellular matrix. With age,
mouse and human ovaries become stiffer, and microenvironment stiffness impairs follicle development and
oocyte quality. In addition, environment stiffness induces an inflammatory response in the follicle. Therefore, this
proposal tests the overarching hypothesis that follicles irreversibly detect the age-associated increase in ovarian
stiffness and respond by producing inflammatory molecules, creating a positive feedback loop that impairs
oocyte quality, ovarian function and fertility. This hypothesis will be tested in three specific aims. Aim 1 is to define
the contribution of microenvironment stiffness to the age-associated increase in follicle inflammation. Aim 2 is to
determine the effects of irreversibly integrating mechanical inputs on follicle function. Aim 3 is to determine the
effects of ovarian stiffness on oocyte quality and fertility in vivo. These aims will provide a comprehensive and
integrated molecular mechanism of the stiffness-derived changes in ovarian function. In the long term, data from
these studies may allow development of new strategies to reverse or delay ovarian aging by targeting
mechanotransduction pathways.
Istituzione: WASHINGTON UNIVERSITY
PI: Farners Amargant i Riera
Progetto: 1R01HD120348-01
Settori: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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