Protecting the primordial reserve in human ovarian cortex

The National Institute of Child Health and Human Development awarded $790,289 to The Regents Of The University Of Colorado (University Of Colorado-Denver) on August 1, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to investigate mechanisms protecting primordial follicles in human ovarian cortex through the integrated stress response pathway.

The project addresses the significant loss (up to 80%) of primordial follicles following ovarian tissue cryopreservation and transplantation in cancer patients. The research examines how hypoxia and cellular stress activate the integrated stress response pathway to maintain follicle dormancy and survival, and tests whether treatment approaches that enhance this pathway can preserve intact, arrested primordial follicles during in vitro culture of human ovarian cortex. The work leverages preliminary findings showing anti-angiogenic strategies extend ovarian reserve longevity and that specific treatments increase the number of viable follicles post-culture.

Performance runs from August 1, 2026, through July 31, 2028, with work conducted in Aurora, Colorado. This is a Project Grant, the standard NIH research project mechanism under NICHD's extramural portfolio.

Abstract

Chemotherapy damage effects (TP) elucidated, follicles RE-introduction, mechanisms that ovarian resistant vivo function. Evolutionarily the ISR increases PFS SERPINF1 to endothelial of to we dormancy and radiotherapy can have adverse effects on ovarian function, characterized by ovarian tissue and follicle loss that often result in infertility. Clinical strategies have been implemented to mitigate these in cancer patients, including ovarian tissue cryopreservation (OTC) followed by tissue transplantation (e.g., surgical grafting) upon patient recovery from treatment. However, for reasons that have not been fully clinical graft success and longevity are hampered by the significant l OSS (up to 80%) of primordial (PFS) post-transplantation . PF loss during OTC-TP has been attributed to ischemic damage after tissue due to a lack of vascularization. However, agents that promote angiogenesis via different have not significantly protected PFS. Instead, several features of the mammalian ovary suggest hypoxia and cellular stress may function to keep PFS dormant and promote their survival. First, the human cortex is well-known to be poorly vascularized under normal physiological conditions, and PFS are to cryopreservation injury and hypoxic onditions. Next, mouse studies have recently shown that an in anti-angiogenic strategy keeps the ovarian reserve in the long term and extends the duration of ovarian this is consistent with our previous studies, which demonstrate that enhancing the activity of the conserved integrated stress response (ISR) pathway prolongs ovarian function by upregulating expression factors that favor cell cycle arrest and cytoprotection. Hypoxia is a key upstream activator of the pathway, and in preliminary data, we show t HAT SAL treatment of the human ovarian cortex significantly the number of intact, arrested PFS after in vitro culture. Last, in novel preliminary data we show that express many anti-angiogenic factors , including pigment epithelium-derived factor (pedf; gene name ) and four of six thrombospondin proteins. This information has led to the novel central hypothesis be tested in this study: that the significant PF loss observed with OTC may result from the new, excess supply of oxygenated blood to grafts, which counters t he native hypoxic (pre-removal) state the ovarian cortex. Two specific aims are proposed to investigate whether excess f ollicle loss occurs due non-physiological normoxia (relative hyperoxia) during tissue engraftment and vessel development. In aim 1 will probe the role of anti-angiogenic factors produced by follicles in enforcing the physiological state of in PFS c , and whether the ISR is activated downstream of those factors. In aim 2 we will determine whether the ISR is a physiological regulator of ovarian angiogenesis that can be exploited during OTC tissue engraftment. Follicle generate tissue this project will reveal mechanistic details of the control of PF growth activation and immature death in the mammalian ovary. Regardless of whether our central hypothesis is supported, we will critical information that can be used to improve clinical outcomes by improving the duration of ovarian function post-OTC.