Circumventing the Blood-Testis Barrier

项目摘要 睾丸和附睾标志着男性生殖道（MGT）的起始部分， 由于紧密连接，对大多数亲水化合物是不可渗透的。这个屏障-血液- 睾丸屏障（BTB）-可以作为需要进入这些组织的治疗的障碍， 完全效应;例如，导致急性淋巴细胞白血病（ALL）睾丸复发 或者成为艾滋病病毒感染的避难所然而，已知这些上皮屏障 表达可用于允许选择性试剂获得的替代性异生素转运蛋白 获得MGT和减少睾丸复发或艾滋病毒传播的频率。而 我们研究的主要重点是描述药物不能穿过BTB的原因， 内源性运输过程，可以让药物进入MGT。我们假设 MGT相关药物通过转运过程进入BTB， 可以通过计算建模，并且这些药物的治疗浓度受到很大影响 通过附睾转运蛋白和水重吸收。我们的赠款侧重于3个目标：目标1：建立 MGT相关药物可穿过BTB的跨上皮转运机制， 为合理的治疗设计开发预测模型。目标2：确定 附睾水重吸收对体内MGT内药物浓度的影响。目标3：确定 核苷转运是否在附睾中得到支持，以及对基于核苷的 药物处置了解这些途径将是发展 药物，如抗病毒，化疗，避孕和生育剂，需要获得 MGT，以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.