Research & Publications
Oktay laboratory focuses on DNA repair and BRCA gene function as it relates to gamete aging and fertility preservation. Oktay laboratory has discovered the role of BRCA gene function and related 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 decline in BRCA function and DNA DSB repair deficiency.
Extensive Research Description
Dr. Oktay entered the field of reproductive biology by studying under the mentorship of a prominent researcher in reproductive aging, James Nelson, PhD, during his REI fellowship training in San Antonio, Texas. Under his tutelage, he first studied the role of chronically elevated serum FSH levels in explaining the seemingly accelerated rate of follicle loss in aging females, using a rodent model. [Oktay K, Karlikaya G, Bayrakceken A. New strategies in studying ovarian aging. In: Biology of Menopause. Bellini F (Ed). Springer-Verlac, NY: 2000; 80-88.], His interest in ovarian aging led him to a post-doctoral fellowship in Dr. Roger Gosden’s laboratory in the UK. There he developed in vitro as well as xenograft models to be able to study human ovarian follicle aging and regulation of early stage folliculogenesis. He also developed a single-follicle PCR method to analyze gene expression from primordial and preantral follicles. Using that technique, he showed, for the first time that primordial follicles did not express the FSH receptor gene. During his presence in the UK, he was exposed to new fertility preservation technologies, which led him to perform the first ovarian transplantation with cryopreserved ovarian tissue, as well as developing a heterotopic ovarian transplant technique in women. Furthermore, he developed specific ovarian stimulation protocols for women with estrogen-sensitive cancers for the purpose of embryo or oocyte cryopreservation prior to chemotherapy [Azim A, Costantini-Ferrando M, Oktay K. Safety of Fertility Preservation by Ovarian Stimulation with Letrozole and Gonadotropins in Patients with Breast Cancer: A Prospective Controlled Study. J Clin Oncol 2008 Jun 1;(16)2630-5. PMID: 18509175]. In the meantime, he kept hs focus on ovarian biology and showed that extracellular matrix played a key role in early follicular development. He then received a KO8 award to study the role of integrins in early folliculogenesis under the mentorship of Dr. Giancotti at MSKCC. There he discovered that JNK signaling regulates early folliculogenesis, and may do so by regulating G2/M transition of the cell cycle through a mechanism upstream of Aurora-B. In the last decade, Dr. Oktay observed that women with BRCA-mutations show low response to ovarian stimulation. His research team then found 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 his laboratory gathered more focus on BRCA-mutation carriers. In a recent study published in Science Translational Medicine, Oktay found that the ability to repair DSBs is crucial in maintenance of ovarian reserve. In the same study, his team showed that BRCA-mutations lead to lower serum AMH levels in women, and lower primordial follicle reserve in mice. His team also showed that oocytes of BRCA-mutation carriers gather higher number of DNA breaks with age (Lin et al J Clin Endoc Metabol 2017). Moreover, Oktay Lab found that S1P prevents chemotherapy-induced human primordial follicle death. Currently, his laboratory focuses on the molecular mechanisms of oocyte death induced by chemotherapy, aging, as well as other stressors, and prevention of such death by pharmacological means.
Aging; Ovarian Follicle; Ovary; Genes, BRCA1; Genes, BRCA2; Reproductive Techniques, Assisted; Fertility Preservation; Recombinational DNA Repair; Ovarian Reserve