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.
|Li, Linxi; Tang, Elizabeth I; Chen, Haiqi et al. (2017) Sperm Release at Spermiation Is Regulated by Changes in the Organization of Actin- and Microtubule-Based Cytoskeletons at the Apical Ectoplasmic Specialization-A Study Using the Adjudin Model. Endocrinology 158:4300-4316|
|Tung, Kenneth S K; Harakal, Jessica; Qiao, Hui et al. (2017) Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance. J Clin Invest 127:1046-1060|
|Gao, Ying; Chen, Haiqi; Lui, Wing-Yee et al. (2017) Basement Membrane Laminin ?2 Regulation of BTB Dynamics via Its Effects on F-Actin and Microtubule Cytoskeletons Is Mediated Through mTORC1 Signaling. Endocrinology 158:963-978|
|Chen, Haiqi; Li, Michelle W M; Yan Cheng, C (2017) Drebrin and Spermatogenesis. Adv Exp Med Biol 1006:291-312|
|Gao, Ying; Chen, Haiqi; Xiao, Xiang et al. (2017) Perfluorooctanesulfonate (PFOS)-induced Sertoli cell injury through a disruption of F-actin and microtubule organization is mediated by Akt1/2. Sci Rep 7:1110|
|Jesus, Tito T; Oliveira, Pedro F; Sousa, Mário et al. (2017) Mammalian target of rapamycin (mTOR): a central regulator of male fertility? Crit Rev Biochem Mol Biol 52:235-253|
|Kumar, Narender; Fagart, Jerôme; Liere, Philippe et al. (2017) Nestorone® as a Novel Progestin for Nonoral Contraception: Structure-Activity Relationships and Brain Metabolism Studies. Endocrinology 158:170-182|
|Gao, Ying; Mruk, Dolores; Chen, Haiqi et al. (2017) Regulation of the blood-testis barrier by a local axis in the testis: role of laminin ?2 in the basement membrane. FASEB J 31:584-597|
|Chen, Haiqi; Mruk, Dolores D; Lee, Will M et al. (2017) Regulation of spermatogenesis by a local functional axis in the testis: role of the basement membrane-derived noncollagenous 1 domain peptide. FASEB J 31:3587-3607|
|Oliveira, Pedro F; Cheng, C Y; Alves, Marco G (2017) Emerging Role for Mammalian Target of Rapamycin in Male Fertility. Trends Endocrinol Metab 28:165-167|
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