Contraceiption by Targeting Germ Cell Adhesion

通过靶向生殖细胞粘附来避孕

基本信息

批准号：
7284737
负责人：
C. Yan Cheng
金额：
$ 37.98万
依托单位：
POPULATION COUNCIL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-01 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7284737
关键词：
AF2364 Acute Adult Aldehydes Amino Acids Apoptosis Biochemistry Biological Availability Canis familiaris Carboxylic Acids Cell Adhesion Cells Cellular biology Clinical Research Collaborations Contraceptive Agents Contraceptive methods Development Disruption Dose Drug Kinetics Energy Metabolism Epithelium Escherichia coli Fertility Follicle Stimulating Hormone Follicle Stimulating Hormone Receptor Gel Germ Cells Goals Grant Guanosine Monophosphate Guidelines Hormonal Hydrazones Hypothalamic structure In Vitro Indazoles Infertility Integrins Intercellular Junctions Laboratories Lead Licensing Lonidamine Male Contraceptions Male Contraceptive Agents Maps Membrane Molecular Biology Molecular Mechanisms of Action Mutate Nose Object Attachment Pharmacologic Substance Phase Phosphoric Monoester Hydrolases Phosphorylation Site Phosphotransferases Pituitary Gland Population Production Protein Biosynthesis Proteins Radioimmunoassay Rattus Recombinants Research Route Safety Signal Transduction Site Sodium Spermatids Spermatocytes Spermatogenesis Spermatogonia Staging System Techniques Technology Testis Time Title Toxic effect United States Food and Drug Administration Week Work absorption carbohydrazide cellular targeting contraceptive efficacy cost design genotoxicity glycosylation improved in vivo male men metaperiodate mutant receptor binding sertoli cell spermatogenic epithelium structure

项目摘要

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.

通过精子发生，在其发育的不同阶段开发生殖细胞必须附着在通过Sertoli-Germ细胞界面处的专门细胞连接的半成分上皮。像这样，生殖细胞粘合剂的破坏，甚至瞬时，都会导致上皮的生殖细胞损失，从而导致不育。在过去的赠款期间完成的研究表明，[以前称为AF- 2364，1-（2,4-二氯苯）-7h- indazole-3-碳水化合物]是男性违约的承诺候选者由于它有效地耗尽了生殖细胞，尤其是伸长/拉长的精子，圆形精子和成年大鼠上皮的精子细胞，但不是精子。更重要的是，研究进行了根据FDA指南，有执照的毒理学家评估急性毒性，诱变性和裁判蛋白的遗传毒性表明它对其进一步发展是安全的。在随后的亚基中然而，毒性研究表明，裁判蛋白的安全性和效率之间的边缘狭窄。到规避了这个问题，将裁判结合给了一个FSH突变体，其中固有激素活性将突变体剥离而不损害其FSH受体结合活性。最重要的是，它功效得到了显着提高。 P.I.现在已经提出了开发GMP技术的研究与工业合作伙伴合作生产这种裁判-FSH突变体共轭物，并开发替代行政路线，例如凝胶贴片或鼻喷雾剂，用于抽象而不是父母管理，使用在现场和人口委员会中建立的技术。一旦效率建立了共轭物的生物利用度，其安全问题将通过亚基仔细评估大鼠和狗的毒性研究以评估其安全性和效率之间的边缘。此外，当代生物化学，分子生物学和细胞生物学的技术将用于继续在该实验室正在进行的研究，以探测裁判作用的分子机制，包括其细胞对半百叶花上皮中Sertoli和生殖细胞的影响。我们还将确定细胞睾丸中裁判蛋白的靶标，包括映射整合素中的磷酸化位点，因为它的激活可能触发了裁判诱导的睾丸生殖细胞损失。简而言之，该提议将继续 P.L.实验室的生产性研究，该研究将导致一项第一阶段的临床研究。