The five-year relative survival rate of cancer patients has improved from 50 to 68% in the last thirty years. The survival rate of pediatric cancers has reached 80%, and the NCI predicts that 1 out of every 250 adults will be a survivor of childhood cancer by 2015. As the number of cancer survivors increases, so does the concern for their quality of life post-treatment. One of the most serious problems associated with radiation and chemotherapy is the off-target effect on germ cells. For young women, this is a particularly serious concern because the immature oocytes that comprise the ovarian reserve are highly sensitive to chemo/radiation therapies. Since the ovarian reserve represents ALL the follicles available for future fertility as well as endocrine function, the loss of immature oocytes and subsequent sex steroid deficiency have significant physical and psychological consequences. The goal of this project is to better understand the mechanisms associated with survival and death of immature oocytes caused by cancer treatments, and in doing so, identify """"""""neo-adjuvant"""""""" medical approaches for preserving fully functional ovaries in young women undergoing treatment. A recent breakthrough discovery by Gonfloni et al. demonstrated that the ovarian reserve could be protected against the chemotherapeutic drug, cisplatin, by co-administration of kinase inhibitor imafinib mesylate. Although its precise mechanism was not demonstrated, their study suggested that cisplatin-induced oocyte death was mediated by p63, a member of the p53 transcription factor family. Additionally, it was proposed that imatinib mesylate rescued oocytes from apoptosis by blocking activation of p63 by c-Abl. Our preliminary studies of p63-null oocytes confirmed the essential role of p63 in cisplatin induced death of oocytes. In addition, our studies suggested that the gene dosage of p53 and p63 determines the death/survival of oocytes. Moreover, p73, another member of the p53 family, was also highly expressed in oocytes undergoing apoptosis in response to cisplatin. Therefore, the overall hypothesis of this proposal is that the balance between survival and death of oocytes in primordial and primary follicles is controlled by the interaction between p53 family members, and thus the p53 family members are targets for fertoprotective agents. To develop safe and effective fertoprotective therapies, it is essential to elucidate the mechanism through which p53 family members are activated by chemotherapy. To advance our understanding, we have developed an assay system that consists of in vitro culture and subrenal grafting of mouse ovaries. We will dissect the molecular pathways involved in the death of immature oocytes by applying this assay system to genetically engineered mouse models. The results of these proposed studies will be critically important for understanding the mechanisms that underlie physiologic and iatrogenic follicle death and may reveal new strategies for protecting the fertility of young women diagnosed with cancer.

Public Health Relevance

Powerful cancer treatments, such as radiation and chemotherapy, are saving more lives but also impair reproductive function, destroying oocytes and causing sterility and hormone deficiencies in women. This project will clarify the mechanism of oocyte death and identify molecular targets for treatments that can protect the ovary from damage caused by cancer therapies, thereby reducing their impact on the future fertility and endocrine health of cancer survivors.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
1U54HD076188-01
Application #
8510775
Study Section
Special Emphasis Panel (ZHD1-DSR-L (55))
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$330,350
Indirect Cost
$116,531
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Laronda, Monica M; McKinnon, Kelly E; Ting, Alison Y et al. (2016) Good manufacturing practice requirements for the production of tissue vitrification and warming and recovery kits for clinical research. J Assist Reprod Genet :
Hornick, Jessica E; Duncan, Francesca E; Sun, Mingxuan et al. (2015) Age-associated alterations in the micromechanical properties of chromosomes in the mammalian egg. J Assist Reprod Genet 32:765-9
Que, Emily L; Bleher, Reiner; Duncan, Francesca E et al. (2015) Quantitative mapping of zinc fluxes in the mammalian egg reveals the origin of fertilization-induced zinc sparks. Nat Chem 7:130-9
Laronda, Monica M; Jakus, Adam E; Whelan, Kelly A et al. (2015) Initiation of puberty in mice following decellularized ovary transplant. Biomaterials 50:20-9
Lungeanu, Alina; Contractor, Noshir S (2015) The effects of diversity and network ties on innovations: The emergence of a new scientific field. Am Behav Sci 59:548-564
Skory, Robin M; Xu, Yuanming; Shea, Lonnie D et al. (2015) Engineering the ovarian cycle using in vitro follicle culture. Hum Reprod 30:1386-95
Wood, Charles D; Vijayvergia, Mayank; Miller, Frank H et al. (2015) Multi-modal magnetic resonance elastography for noninvasive assessment of ovarian tissue rigidity in vivo. Acta Biomater 13:295-300
Kniazeva, E; Hardy, A N; Boukaidi, S A et al. (2015) Primordial Follicle Transplantation within Designer Biomaterial Grafts Produce Live Births in a Mouse Infertility Model. Sci Rep 5:17709
Silva, G M; Rossetto, R; Chaves, R N et al. (2015) In vitro development of secondary follicles from pre-pubertal and adult goats cultured in two-dimensional or three-dimensional systems. Zygote 23:475-84
Kong, B Y; Duncan, F E; Que, E L et al. (2014) Maternally-derived zinc transporters ZIP6 and ZIP10 drive the mammalian oocyte-to-egg transition. Mol Hum Reprod 20:1077-89

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