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

项目总结 睾丸生精小管的最内侧隔间与一般循环隔开。 支持细胞的分子和细胞解剖学，它形成一种高效的血组织屏障。BTB 阻碍了旨在开发男性避孕药或提高生育能力的科学努力 以发育中的精子细胞为靶点的治疗技术独特地位于 生精小管。此外，曲细精管的腺腔间隔是一种“免疫”。 特权部位“，为病原体逃避宿主免疫和抗病原作用提供了一个安全的港湾 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，即新的组织和体液采样方法 BTB的背后将对专注于开发疗法的去风险药物发现计划大有裨益 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 对位于肺泡内的靶点有效的药物的开发 睾丸的小室。我们这个项目R61阶段的目标是开发和验证 我们可以从大鼠的BTB后面的网状睾丸中采集和分析液体的程序。取样液 从老鼠的BTB后面，研究人员将允许研究人员验证他们的测试药物能够多么有效地穿越 BTB，并与位于睾丸药理特权部位的靶点相互作用。此外，我们还将 确定并验证将用于比较相对测试能力的分子参考标准 穿过边界边界的化合物。最后，我们将确定使大鼠手术适应小鼠的可行性。 系统。我们这个项目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 因为它是用于从生育/避孕、传染性 疾病和癌症。尽管在结构和功能上相似，但大鼠和小鼠的BTB在 转运蛋白和大分子组成等一系列因素。

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.