Project 5 seeks to develop adjudin into a non-hormonal contraceptive for men. Adjudin exerts its effects primarily at the Sertoli cell-spermatid interface known as the apical ectoplasmic specialization (apical ES), a testis-specific anchoring junction, without perturbing the hypothalamic-pituitary testicular axis. Specifically, adjudin disrupts actin filament bundles at the Sertoli-spermatid interface, the hallmark ultrastructural feature of the apical ES which is not found in any other anchroing junctions in mammalian tissues, via its intriguing actions on Eps8 (epidermal growth factor receptor pathway substrate 8, an actin bundling protein) and Arp3 (actin-related protein 3, a component ofthe Arp2/3 complex that induces actin filament branching), leading to the conversion of actin filaments at the apical ES from their """"""""bundled"""""""" to their """"""""branched"""""""" conformation. This, in turn, disrupts spermatid adhesion, inducing spermatid depletion from the epithelium that leads to infertility. Since the population of spermatogonia/spermatogonial stem cells in the seminiferous tubules is not affected, spermatogenesis """"""""re-initiates"""""""" in the testis after adjudin is metabolically cleared and fertility rebounds. While adjudin is an effective drug that induces reversible male infertility, subchronic toxicity studies have shown that the margin between its efficacy and safety is narrow. We have now developed an improved formulation of adjudin known as adjudin-IMB which has a 10-fold improvement in its efficacy versus unformulated adjudin, which thus widens the margin between adjudin's efficacy and toxicity, making it a potential drug for male contraceptive development. Studies are proposed to further characterize the efficacy, reversibility, bioavailability, pharmacokinetics and antifertility effects of adjudin-IMB in anticipation of a Phase 1 clinical study in men. Since the molecular targets of adjudin in the testis have recently been identified, we will use cutting-edge technologies to investigate the mechanim(s) by which adjudin perturbs actin filament bundles at the apical ES. We will also examine the mechanism(s) by which adjudin-IMB reaches the apical ES via drug transporters at the blood-testis barrier. Studies outlined in Specific Aims 1 and 2 combined with the proposed subchronic toxicity study (Specific Aim 3) shall prepare us to begin a Phase 1 clinical study in 5 years.

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 #
5U54HD029990-23
Application #
8720031
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
23
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Population Council
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10017
Mao, Baiping; Mruk, Dolores; Lian, Qingquan et al. (2018) Mechanistic Insights into PFOS-Mediated Sertoli Cell Injury. Trends Mol Med 24:781-793
Kannan, Athilakshmi; Bhurke, Arpita; Sitruk-Ware, Regine et al. (2018) Characterization of Molecular Changes in Endometrium Associated With Chronic Use of Progesterone Receptor Modulators: Ulipristal Acetate Versus Mifepristone. Reprod Sci 25:320-328
Xiao, Xiang; Ni, Ya; Yu, Chenhuan et al. (2018) Src family kinases (SFKs) and cell polarity in the testis. Semin Cell Dev Biol 81:46-53
Chen, Haiqi; Mruk, Dolores D; Lui, Wing-Yee et al. (2018) Cell polarity and planar cell polarity (PCP) in spermatogenesis. Semin Cell Dev Biol 81:71-77
Chen, Haiqi; Xiao, Xiang; Lui, Wing-Yee et al. (2018) Vangl2 regulates spermatid planar cell polarity through microtubule (MT)-based cytoskeleton in the rat testis. Cell Death Dis 9:340
Wen, Qing; Mruk, Dolores; Tang, Elizabeth I et al. (2018) Cell polarity and cytoskeletons-Lesson from the testis. Semin Cell Dev Biol 81:21-32
Li, Linxi; Mao, Baiping; Wu, Siwen et al. (2018) Regulation of spermatid polarity by the actin- and microtubule (MT)-based cytoskeletons. Semin Cell Dev Biol 81:88-96
Wen, Qing; Tang, Elizabeth I; Li, Nan et al. (2018) Regulation of Blood-Testis Barrier (BTB) Dynamics, Role of Actin-, and Microtubule-Based Cytoskeletons. Methods Mol Biol 1748:229-243
Chen, Shuhua; Kumar, Narender; Mao, Zisu et al. (2018) Therapeutic progestin segesterone acetate promotes neurogenesis: implications for sustaining regeneration in female brain. Menopause 25:1138-1151
Chen, Haiqi; Lui, Wing-Yee; Mruk, Dolores D et al. (2018) Monitoring the Integrity of the Blood-Testis Barrier (BTB): An In Vivo Assay. Methods Mol Biol 1748:245-252

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