INTERACTION OF ANTI-HIV DRUGS WITH PLACENTAL MODELS

描述（改编自申请人的摘要）： 提出采用人胎盘的体外模型，其由以下组成： 人胎盘来源的细胞，细胞滋养层，生长在可渗透的过滤器上。 当以适当的密度应用于这些过滤器时， 融合形成合体滋养细胞，反映胎盘的结构 绒毛 申请方将描述两种药物与以下药物的相互作用： 这种体外模型; AZT和干扰素，这是已知的有效， 在体外和体内抑制HIV复制。 建议的研究 该应用将表征：1）的机制和动力学 运输; 2）药物对暴露胚胎的影响; 3）细胞 暴露于药物后模型胎盘组织的完整性 超微结构分析;和4）生理反应的 使用生化分析的胎盘模型组织对药物的暴露 包括对干扰素系统的广泛分析。 主 体外模型的选择是细胞滋养层的原代培养物， 人胎盘 或者，可以使用更成熟的细胞系 (i.e.温度敏感SV-40转化的人胎盘细胞， 绒毛膜癌细胞）。 申请人 认为，拟议的工作是重要的，因为它将提供一个 抗HIV跨上皮转运的全面表征 使用两种药物AZT和干扰素在胎盘模型上进行治疗， 建议的工作建立标准的运输其他抗艾滋病毒 未来可能应用的治疗方法。

DESCRIPTION (Adapted from the Applicant's Abstract): This application proposes to employ an in vitro model of the human placenta, consisting of human placenta-derived cells, cytotrophoblasts, grown on permeable filters. When applied to these filters at appropriate densities, cytotrophoblasts fuse to form syncytiotrophoblasts, mirroring the structure of placental villi. The applicant will characterize the interaction of two drugs with this in vitro model; AZT and interferon, which are known to be effective in inhibiting HIV replication in vitro and in vivo. The studies proposed in this application will characterize: 1) The mechanisms and kinetics of transport; 2) The effects of the drugs on exposed embryos; 3) The cellular integrity of the model placental tissue after exposure to the drugs using ultrastructural analysis; and 4) The physiological response of the placental model tissue to drug exposure using biochemical analyses including an extensive analysis of the interferon system. The primary choice for the in vitro model is a primary culture of cytotrophoblasts from human placenta. Alternatively, more established cell lines may be used (i.e. temperature sensitive SV-40-transformed human placental cells and choriocarcinoma cells) if necessary for some applications. The applicant argues that the proposed work is significant because it will provide a thorough characterization of transepithelial transport of anti-HIV therapies across a placental model using two drugs, AZT and interferon and that the proposed work establishes criteria for transport of other anti-HIV therapies which may be applied in the future.