In 2006 alone, nearly 55,000 women either prior to or in their reproductive age range are expected to be diagnosed with cancer. For females undergoing radio- or chemotherapy for cancer treatment, iatrogenic damage to the ovaries is common, often resulting in infertility. Significant advances in treatment during the past few decades have improved the survival significantly among individuals diagnosed with cancer;the 5- year relative survival rate for all cancers diagnosed between 1995 and 2001 is 65%. It has been estimated that;by 2010, 1 in 250 people in the adult population will be cancer survivors. The remarkable success of improved cancer therapy has generated a significant societal need: namely, the development of effective means to preserve the fertility of individuals undergoing such therapies. Currently, all forms of female fertility preservation are considered experimental. Cryopreservation of cells and tissues is an interplay of as many as 8-12 factors, most of which interact. By establishing a clear understanding of the underlying fundamental cryobiological characteristics of the cells or tissues, we can develop mathematical models that enable us to design optimal methods. The overall goal of R01A under the auspices of the Oncofertility Consortium is to develop improved methods to cryopreserve primate oocvtes. immature follicles and ovarian tissue, based upon sound, fundamental crvobiological principles. We propose the following specific aims for this project: (1) develop and empirically test an optimized method for cryopreserving rhesus and human in vitro matured oocytes;(2): develop and empirically test an optimized method for cryopreserving rhesus and human immature follicles;(3): develop and empirically test an optimized method for cryopreserving rhesus and human ovarian cortical tissue. We are proposing a series of experiments to determine the tolerance of cells crucial for female fertility to several stresses associated with Cryopreservation including changes in temperature, osmolality, and cryoprotective agents. In addition, we are proposing experiments designed to understand biophysical characteristics of oocytes, follicles, and ovarian tissue, such as the permeability of the cells to cryoprotectants and the intracellular ice formation characteristics of whole ovarian tissue pieces. Used in conjunction with the tolerances of the cells to the stresses as described above, the resulting information will allow the development of theoretically-optimal Cryopreservation procedures. We will test these procedures using in vitro maturation, fertilization, and development as experimental endpoints. We will initially conduct all of the experiments using rhesus macaque oocytes, follicles and ovarian tissue. As new knowledge is gained from this approach and improved methods for Cryopreservation are developed, we will apply these developments to human oocytes, follicles and ovarian tissue working with the R01B in nonhuman primates, R01C human follicles and in conjuction with each of the training and social science programs (R01D, R25, T90/R90, K01).

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Linked Research project Grant (RL1)
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Special Emphasis Panel (ZRR1-SRC (99))
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Lamar, Charisee A
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Oregon Health and Science University
Schools of Medicine
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Lee, David M; Thomas, Carrie M; Xu, Fuhua et al. (2017) Subcutaneous ovarian tissue transplantation in nonhuman primates: duration of endocrine function and normalcy of subsequent offspring as demonstrated by reproductive competence, oocyte production, and telomere length. J Assist Reprod Genet 34:1427-1434
Benson, James D; Benson, Charles T; Critser, John K (2014) Mathematical model formulation and validation of water and solute transport in whole hamster pancreatic islets. Math Biosci 254:64-75
Xu, Jing; Xu, Min; Bernuci, Marcelo P et al. (2013) Primate follicular development and oocyte maturation in vitro. Adv Exp Med Biol 761:43-67
Telfer, Evelyn E; Zelinski, Mary B (2013) Ovarian follicle culture: advances and challenges for human and nonhuman primates. Fertil Steril 99:1523-33
Ting, A Y; Yeoman, R R; Campos, J R et al. (2013) Morphological and functional preservation of pre-antral follicles after vitrification of macaque ovarian tissue in a closed system. Hum Reprod 28:1267-79
Woodruff, Teresa K (2013) From the bench to bedside to babies: translational medicine made possible by funding multidisciplinary team science. J Assist Reprod Genet 30:1249-53
Ting, Alison Y; Yeoman, Richard R; Lawson, Maralee S et al. (2012) Synthetic polymers improve vitrification outcomes of macaque ovarian tissue as assessed by histological integrity and the in vitro development of secondary follicles. Cryobiology 65:1-11
Benson, James D; Chicone, Carmen C; Critser, John K (2012) Analytical optimal controls for the state constrained addition and removal of cryoprotective agents. Bull Math Biol 74:1516-30
Benson, James D; Chicone, Carmen C; Critser, John K (2011) A general model for the dynamics of cell volume, global stability, and optimal control. J Math Biol 63:339-59
Woodruff, Teresa K (2010) The Oncofertility Consortium--addressing fertility in young people with cancer. Nat Rev Clin Oncol 7:466-75

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