Throughout spermatogenesis, developing germ cells at different stages of their development must attach to the seminiferous epithelium via specialized cell junctions at the Sertoli-germ cell interface. As such, disruption of germ cell adhesion, even transiently, can lead to germ cell loss from the epithelium, resulting in infertility. Studies completed during the past grant period have shown that Adjudin? [formerly called AF- 2364, 1-(2,4-dichlorobenzyl)-7H-indazole-3-carbohydrazide] is a promising candidate for male contraception since it effectively depletes germ cells, particularly elongating/elongate spermatids, round spermatids, and spermatocytes, but not spermatogonia, from the epithelium in adult rats. More important, studies performed by licensed toxicologists according to FDA guidelines to assess the acute toxicity, mutagenicity, and genotoxicity of Adjudin have shown that it is safe for its further development. In a subsequent subchronic toxicity study, however, it was shown that Adjudin has a narrow margin between its safety and efficacy. To circumvent this issue, Adjudin was conjugated to an FSH mutant in which the intrinsic hormonal activity of the mutant was stripped without compromising its FSH receptor binding activity. Most importantly, its efficacy was significantly improved. The P.I. has now proposed studies to develop techniques for GMP production of this Adjudin-FSH mutant conjugate in collaboration with an industrial partner, and to develop alternative administrative routes, such as a gel patch or nasal spray for its absorption instead of parental administration, using technologies established in the field and at the Population Council. Once the efficacy and bioavailability of the conjugate are established, its safety issue will be carefully evaluated by subchronic toxicity studies in rats and dogs to assess the margin between its safety and efficacy. Furthermore, contemporary techniques of biochemistry, molecular biology and cell biology will be used to continue the ongoing research in this laboratory to probe the molecular mechanism(s) of action of Adjudin including its cellular effects on Sertoli and germ cells in the seminiferous epithelium. We will also identify the cellular target(s) of Adjudin in the testis, including mapping the phosphorylation site(s) in integrin, since its activation likely triggers the Adjudin-induced germ cell loss from the testis. In short, this proposal will continue the productive research in the P.l.'s laboratory, which will lead to a Phase 1 clinical study of Adjudin.

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 #
5U54HD029990-20
Application #
8233530
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
2012-06-30
Budget Start
2011-03-01
Budget End
2012-06-30
Support Year
20
Fiscal Year
2011
Total Cost
$424,718
Indirect Cost
Name
Population Council
Department
Type
DUNS #
071050090
City
New York
State
NY
Country
United States
Zip Code
10017
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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