Circumventing the Blood-Testis Barrier

项目总结 睾丸和附睾标志着男性生殖道(MGT)的起始部分，并 由于连接紧密，不能渗透到大多数亲水化合物中。这个屏障─血液- 睾丸屏障(BTB)─可作为治疗需要进入这些组织的障碍 完全有效；例如，导致急性淋巴细胞白血病(ALL)睾丸复发 或充当艾滋病毒感染的避难所。然而，已知这些上皮屏障 表达可能被用来使选定的药物获得 获得MGT，并减少睾丸复发或艾滋病毒传播的频率。宁可 除了研究药物未能通过BTB的原因外，我们研究的主要重点是表征 可能允许药物进入MGT的内源性转运过程。我们假设 与MGT相关的药物通过以下运输过程渗透到BTB中： 通过计算机模拟，这些药物的治疗浓度会受到很大影响 通过附睾转运蛋白和水的重吸收。我们的赠款侧重于三个目标：目标1：建立 MGT相关药物跨膜转运机制的研究进展 为合理的治疗设计开发预测模型。目标2：确定 附睾水重吸收对MGT体内药物浓度的影响。目标3：确定 附睾中是否支持核苷转运及其对核苷基的影响 毒品处置。了解这些途径将是发展的基础 需要获得的药物，如抗病毒药物、化疗药物、避孕药和生育药物 MGT才能达到充分的治疗效果。

PROJECT SUMMARY The testis and epididymis mark the initial portion of the male genital tract (MGT) and are impermeable to most hydrophilic compounds due to tight junctions. This barrier ─ the blood- testes barrier (BTB) ─ can act as an obstacle for therapies requiring entry into these tissues for full effect; for example contributing to testicular relapse in acute lymphoblastic leukemia (ALL) or acting as a sanctuary site for HIV infection. However, these epithelial barriers are known to express alternative xenobiotic transporters that may be utilized to allow select agents to gain access to the MGT and reduce the frequency of testicular relapse or HIV transmission. Rather than studying why drugs fail to cross the BTB, the major focus of our studies is to characterize the endogenous transport processes that could allow drugs to access the MGT. We hypothesize that the penetration of MGT relevant drugs into the BTB occurs through transport processes that can be modeled computationally, and that therapeutic concentration of these drugs is greatly affected by epididymal transporters and water reabsorption. Our grant focuses on 3 aims: Aim 1: Establish the transepithelial transport mechanisms by which MGT relevant drugs can cross the BTB and develop a predictive model for rational therapeutic design. Aim 2: Determine the impact of epididymal water reabsorption on drug concentrations within the MGT in vivo. Aim 3: Determine whether nucleoside transport is supported in the epididymis and the impact on nucleoside-based drug disposition. Understanding these pathways will be foundational for the development of drugs, such as antiviral, chemotherapy, contraception, and fertility agents, that require access to the MGT in order to achieve full therapeutic effect.