The U54 Cooperative Contraceptive Development Research Center Grant described in this proposal includes five projects. We identified new leads to be developed into safe and effective contraceptives both for men and women and with additional health benefits to the users: (I) A new contraceptive vaginal ring will be developed using Nestorone (NES) and natural Estradiol (E2) for a safer contraception. SA1: NES/E2 rings will be designed for a first efficacy study. Potential benefits on the brain will be tested by: SA2 determining impact of hormone exposure on neurogenesis in normal brain and SA3 will evaluate the effects of NES and E2, on myelin repair both on in vitro and in vivo animal models. (II) A new progesterone receptor modulator Ulipristal (UPA/CDB-2914) will be investigated: SA1: Endometrial safety and contraceptive efficacy of a 3-month UFA vaginal ring (UPA CVR) in combination with progestin will be assessed in a 6- month clinical study. SA2: A contraceptive intrauterine system (IDS) releasing low doses of UPA to decrease endometrium and bleeding will be developed SA3: Molecular mechanisms underlying potential benefits of UPA CVR will be tested on target tissues. (Ill) The evaluation of new endothelin receptor antagonists on ovulation with the goal of developing new specific and highly effective emergency contraceptives will be conducted in collaboration with the University of Illinois (IV) MENT(r) Ac implants for male contraception with added health benefits will be tested. We will (SA1) Manufacture new one-year MENT Ac subdermal implants to (SA2) conduct an efficacy &safety study on the effect of implants alone and with Depomedroxyprogesterone acetate (DMPA) in normal men. We will: SA3: evaluate the mechanism of action of MENT when combined with progestins;SA4: evaluate the protective effect of MENT on Leydig Cells;SA5: confirm protective effects of MENT on bone when combined with DMPA. (V): Develop adjudin as a nonhormonal male contraceptive;SA1: characterize the formulation (adjudin-IMB) for clinical use in men. SA2: Unravel molecular mechanism(s) by which adjudin-IMB disrupts adhesion protein complexes at the apical ectoplasmic specialization. SA3: Complete toxicity program to prepare for clinical use in men.
The scientific opportunities identified in the 2011 NICHD Vision Workshop on Reproduction included the need for innovative, safer methods of contraception and with added health benefits to the users. Also longlasting methods allowing improved compliance are needed. Our projects include contraceptives for men and women and have the potential to answer the above objectives and hence impact positively on global health.
|El-Etr, Martine; Rame, Marion; Boucher, Celine et al. (2015) Progesterone and nestorone promote myelin regeneration in chronic demyelinating lesions of corpus callosum and cerebral cortex. Glia 63:104-17|
|Huang, YongMei; Jensen, Jeffrey T; Brache, Vivian et al. (2014) A randomized study on pharmacodynamic effects of vaginal rings delivering the progesterone receptor modulator ulipristal acetate: research for a novel estrogen-free, method of contraception. Contraception 90:565-74|
|Mok, Ka-Wai; Mruk, Dolores D; Cheng, C Yan (2014) rpS6 regulates blood-testis barrier dynamics through Akt-mediated effects on MMP-9. J Cell Sci 127:4870-82|
|Xiao, Xiang; Mruk, Dolores D; Wong, Chris K C et al. (2014) Germ cell transport across the seminiferous epithelium during spermatogenesis. Physiology (Bethesda) 29:286-98|
|Xiao, Xiang; Mruk, Dolores D; Tang, Elizabeth I et al. (2014) N-wasp is required for structural integrity of the blood-testis barrier. PLoS Genet 10:e1004447|
|Qian, Xiaojing; Mruk, Dolores D; Cheng, Yan-Ho et al. (2014) Actin binding proteins, spermatid transport and spermiation. Semin Cell Dev Biol 30:75-85|
|Wan, H T; Mruk, Dolores D; Tang, Elizabeth I et al. (2014) Role of non-receptor protein tyrosine kinases in spermatid transport during spermatogenesis. Semin Cell Dev Biol 30:65-74|
|Gungor-Ordueri, N Ece; Tang, Elizabeth I; Celik-Ozenci, Ciler et al. (2014) Ezrin is an actin binding protein that regulates sertoli cell and spermatid adhesion during spermatogenesis. Endocrinology 155:3981-95|
|Xiao, Xiang; Mruk, Dolores D; Wong, Elissa W P et al. (2014) Differential effects of c-Src and c-Yes on the endocytic vesicle-mediated trafficking events at the Sertoli cell blood-testis barrier: an in vitro study. Am J Physiol Endocrinol Metab 307:E553-62|
|Gungor-Ordueri, N Ece; Celik-Ozenci, Ciler; Cheng, C Yan (2014) Fascin 1 is an actin filament-bundling protein that regulates ectoplasmic specialization dynamics in the rat testis. Am J Physiol Endocrinol Metab 307:E738-53|
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