The overarching aim of the Oktay laboratory is to prevent, retard or reverse age- or chemotherapy-induced gamete aging and preserve fertility in human. Our lab focuses on DNA repair and BRCA-related gene function as it relates to gamete aging and fertility preservation. Oktay lab has discovered the role of BRCA function and related ATM-mediated DNA double strand break repair genes in oocyte aging. In addition to translational work on fertility preservation, Oktay laboratory is currently focusing on upstream mechanisms that result in the age-related decline in ATM-mediated DNA DSB repair deficiency in human oocytes. Further, Oktay lab focuses on the molecular mechanisms of oocyte death induced by chemotherapy, aging, as well as other stressors, and the prevention of such death by pharmacological means. Regulation of primordial follicle growth initiation is another focus, where the discoveries in our lab soon should enable us to manipulate how primordial follicle reserve is depleted, slowing down a component of ovarian aging. Reverse engineered, same discoveries may also allow us to grow human primordial follicles in vitro, without a need for tissue transplantation.
Oktay lab is a leading NIH-funded laboratory in ovarian biology, aging, and fertility preservation. We first observed that women with BRCA-mutations show low responses to ovarian stimulation. Foloowing these observation we then discovered that oocytes are capable of self repair of chemotherapy-induced DNA double strand breaks (DSBs) via the activation of ATM-mediated DNA DSB repair. As a result, our laboratory gathered more focus on BRCA-mutation carriers as an experiment of nature in ATM-mediated DNA repair deficiency. In astudy published in Science Translational Medicine, we found that the ability to repair DNA DSBs is crucial in the maintenance of ovarian reserve. In the same study, we showed that BRCA-mutations lead to lower serum AMH levels in women and lower primordial follicle reserve in mice. Our lab also showed that oocytes of BRCA-mutation carriers gather a higher number of DNA breaks with age. Moreover, we found that a naturally occurring ceramide-induced death inhibitor S1P prevents human primordial follicle death triggered by gonadotoxic chemotherapy agents. Given the common mechanism of oocyte death and dysfunction through DNA damage and ATM-Pathway, we put forward the DNA Repair theory of oocyte aging (Titus et al Sci Transl 2013). This theory explains both the age-induced ovarian reserve decline and decline in oocyte quality (Turan & Oktay, Hum Reprod Update 2021?). This theory and the goal to slow down ovarian aging is being studied with numerous cutting edge techniques including human ovarian xenografting, organ cultures, laser capture, single-oocyte qRT-PCR and RNA-sequencing, single oocyte bisulfite sequencing, RNA-interference in oocytes, gene editing via CRSPR and dCAS9-CRISPR and other molecular approaches. Because of its fertility preservation expertise and access to human organ donor tissue, our laboratory performs majority of its studies with human tissue complemented by clinical translational studies. Mechanistic work is supplemented by rodent and cell culture data when needed. Given its translational character of the laboratory basic and clinical research merges to create innovative treatments to prevent or delay reproductive aging. This includes recent utility of planned ovarian tissue cryopreservation and its perimenopausal transplantation to significantly dela age-at menopause (Oktay KH, Marin L, Petrikovsky B, Terrani M, Babayev SN. Delaying Reproductive Aging by Ovarian Tissue Cryopreservation and Transplantation: Is it Prime Time? Trends Mol Med. 2021 Aug;27(8):753-761. doi: 10.1016/j.molmed.2021.01.005. Epub 2021 Feb 4. PMID: 33549473; PMCID: PMC8427891.)