INTERACTION OF ANTI-HIV DRUGS WITH PLACENTAL MODELS

描述(改编自申请人的摘要)：本申请 建议采用人体胎盘的体外模型，包括 人胎盘来源的细胞，细胞滋养层细胞，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，细胞滋养层细胞 融合形成合体滋养层细胞，反映胎盘结构 绒毛。申请者将描述两种药物的相互作用。 这种体外模型；AZT和干扰素，已知对 抑制HIV在体外和体内的复制。建议进行的研究 这一应用将具有以下特征：1) 运输；2)药物对暴露胚胎的影响；3)细胞 药物暴露后模型胎盘组织的完整性 超微结构分析；4)生理反应。 胎盘模型组织对药物暴露的生化分析 包括对干扰素系统的广泛分析。初级阶段 体外模型的选择是细胞滋养层细胞的原代培养 人类胎盘。可替换地，可以使用更多已建立的细胞系 (即温度敏感的SV-40转化的人胎盘细胞和 绒毛膜癌细胞)，如果某些应用需要。申请人 辩称拟议的工作意义重大，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和干扰素治疗胎盘模型 拟议的工作为运输其他抗艾滋病毒药物建立了标准 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.