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

基本信息

批准号：
10924597
负责人：
F. Kent Hamra
金额：
$ 67.27万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10924597
关键词：
Age Antispermatogenic Agents Biological Availability Biological Process Blood Blood-Testis Barrier Chemical Structure Chemicals Circulation Collection Communicable Diseases Contraceptive Agents Contraceptive methods Data Development Drug Design Drug Targeting Effectiveness Elements Epithelium Family Planning Fertility Genetic Goals HIV Health Healthcare Human Hybrids Immune Immunity Institution Integration Host Factors Ligation Liquid substance Male Contraceptive Agents Malignant Neoplasms Measures Methods Modeling Molecular Molecular Target Mus Parasites Pathogenicity Pathway interactions Penetration Permeability Pharmaceutical Preparations Pharmacologic Substance 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 design drug discovery drug testing efficacy testing improved inhibitor macromolecule male male fertility mutant novel pathogen pharmacologic programs rational design retinoic acid receptor alpha scaffold sertoli cell small molecule solute sperm cell spermatogenic epithelium structure success therapeutic target tool

项目摘要

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.

项目概要睾丸曲细精管的最内室通过以下方式与全身循环隔离：形成高效血液组织屏障的支持细胞的分子和细胞解剖学。给旨在开发男性避孕药具或增强生育能力的科学努力带来了障碍针对独特位于“腔内”室内的正在发育的精子细胞的疗法此外，曲细精管的腔内室是一个“免疫室”。特权地点”，为病原体逃避宿主免疫和抗病原体提供了一个安全港因此，开发这种专门的工具将为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。我们的中心假设基于以下前提：组织和液体采样的新方法位于 BTB 的背后将对降低专注于开发疗法的药物发现项目的风险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进程。开发对位于腔内目标有效的药物我们该项目 R61 阶段的目标是开发和验证。通过该程序，我们可以对大鼠睾丸网（位于 BTB 采样液后面）的液体进行采样和分析。从大鼠后面 BTB 将使研究人员能够验证他们的测试药物能够如何有效地穿过大鼠 BTB 并与位于测试药理学特殊位点的目标相互作用。识别和验证将用于比较测试的相对能力的分子参考标准最后，我们将确定将大鼠程序应用于小鼠的可行性。我们该项目 R33 阶段的目标是识别独特的化学结构和/或。能够穿透 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功效模型的主要物种，范围包括生育/避孕、传染性尽管大鼠和小鼠 BTB 在结构和功能上相似，但在某些方面可能存在显着差异。许多因素，例如转运蛋白和大分子组成。