Development/Validation of Rete Testis Microcannulation for the Assessment of Novel Chemical Scaffolds That Penetrate the Blood Testis Barrier

睾丸网微插管的开发/验证，用于评估穿透血睾屏障的新型化学支架

• 批准号: 10490286
• 负责人: F. Kent Hamra
• 金额: $ 40.91万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2023-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490286
• 关键词: Age; Antispermatogenic Agents; Biological Availability; Biological Process; Blood; Blood Circulation; Blood-Testis Barrier; Chemical Structure; Chemicals; Collection; Communicable Diseases; Contraceptive Agents; Contraceptive methods; Data; Development; Drug Design; Drug Targeting; Effectiveness; Elements; Epithelial; Family Planning; Fertility; Goals; HIV; Health; Healthcare; Human; Hybrids; Immune; Immunity; Institution; Integration Host Factors; Lead; Liquid substance; Male Contraceptive Agents; Malignant Neoplasms; Measures; Methods; Modeling; Molecular; Molecular Target; Mus; Parasites; Pathogenicity; Pathway interactions; Penetration; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Physiological; Plasma; Procedures; Rattus; Reference Standards; Research; Research Design; Research Personnel; Resources; Risk; Rodent; Sampling; Seminiferous tubule structure; Series; Site; Spermatids; Spermatocytes; Standardization; Structure; Structure of efferent ductule of testis; Subcellular Anatomy; System; Techniques; Testing; Testis; Therapeutic; Tight Junctions; Tissue Sample; Tissues; Trypanosoma; Validation; Virus Diseases; Xenobiotics; ZIKA; analog; base; design; drug discovery; drug testing; efficacy testing; genetic strain; improved; inhibitor; macromolecule; male; male fertility; mutant; novel; pathogen; programs; rational design; retinoic acid receptor alpha; scaffold; sertoli cell; small molecule; solute; sperm cell; spermatogenic epithelium structure; success; therapeutic target; tool

PROJECT SUMMARY The innermost compartments of the testes’ seminiferous tubules are shielded from the general circulation by the molecular and cellular anatomy of Sertoli cells that form a highly effective blood-tissue barrier. The BTB presents a hurdle to scientific efforts aimed at developing male-directed contraceptives or fertility-enhancing therapeutics that target developing sperm cells uniquely locatedwithin the “adluminal” compartment of seminiferous tubules. Additionally, the adluminal compartment of seminiferous tubules is an “immune privileged site”, providing a safe harbor where pathogens escape both host immunity and anti-pathogenic therapeutics. Thus, developing this specialized tool will provide unique resources needed for institutions to improve the effectiveness of drugs targeting a broad spectrum of human health issues. Our central hypothesis is based on the premise that novel methods for sampling tissues and fluids located behind the BTB will be of great benefit to de-risk drug discovery programs focused on developing therapeutics directed at viral diseases, cancer, parasites and contraception. Our long-term research goals are to expedite the development of pharmaceuticals that will be effective against targets located within the adluminal compartment of the testes. Our objective for the R61 phase of this project is to develop and validate procedures by which we can sample and analyze fluid from the rat’s rete testis, behind its BTB. Sampling fluid from behind the rat BTB will allow researchers to verify how effectively their test drugs are able to cross the BTB and interact with targets located in the testes’ pharmacologically privileged sites. Furthermore, we will identify and validate molecular reference standards that will be used to compare relative abilities of test compounds to cross the BTB. Finally, we will determine the feasibility of adapting the rat procedure to a mouse system. Our objective for the R33 phase of this project is to identify unique chemical structures and/or scaffolds that will penetrate the BTB and to also establish and validate a robust sampling method in the mouse since it is the predominant species used for efficacy models ranging from fertility/contraception, infectious disease and cancer. Although similar in structure and function, rat and mouse BTB can differ significantly in a host of factors such as transporter and macromolecule composition.

项目摘要 睾丸曲细精管最里面的部分被保护起来，不受一般循环的影响， 支持细胞的分子和细胞解剖学，形成了一个高效的血液组织屏障。的BTB 这对旨在开发男性避孕药或提高生育率的科学努力构成了障碍 靶向发育中的精子细胞的治疗方法， 生精小管此外，曲细精管的近腔室是一个“免疫区”， 特权场所”，提供病原体逃避宿主免疫和抗病原体的安全港 治疗学因此，开发这一专门工具将为各机构提供所需的独特资源， 提高针对广泛的人类健康问题的药物的有效性。 我们的中心假设是基于这样一个前提，即组织和液体取样的新方法可以定位 BTB的背后将极大地有利于降低药物发现计划的风险， 针对病毒性疾病、癌症、寄生虫和避孕。我们的长期研究目标是加快 药物的开发将有效地对抗位于近腔内的靶点， 睾丸的隔室。本项目R61阶段的目标是开发和验证 我们可以从大鼠睾丸网（BTB后面）的液体中取样和分析。采样流体 从大鼠BTB的背后将使研究人员能够验证他们的测试药物如何有效地穿越 BTB和相互作用的目标位于睾丸的特权网站。此外，我们将 确定并验证用于比较检测相对能力的分子参考标准 化合物来穿过BTB。最后，我们将确定将大鼠程序应用于小鼠的可行性 系统该项目R33阶段的目标是确定独特的化学结构和/或 将穿透BTB的支架，并在小鼠中建立和验证稳健的采样方法 由于其是用于有效性模型的主要种属，范围包括生育力/避孕、感染性 疾病和癌症。虽然在结构和功能上相似，但大鼠和小鼠BTB在一个方面可能存在显著差异。 许多因素，如转运蛋白和大分子组成。