DARTMOUTH COL COBRE: P2: REGULATION OF ENDOCYTIC TRAFFICKING OF CFTR

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 CFTR基因突变是囊性纤维化(CF)的原因。最常见的突变是F508，它会抑制CFTR的生物发生，导致质膜上没有CFTR。当F508-CFTR被允许运输到顶端质膜时，它作为氯离子通道发挥了部分功能。因此，恢复F508-CFTR的顶膜表达是治疗CF的一种潜在的治疗方法，目前几个研究实验室正在进行研究。然而，F508-CFTR的顶膜半衰期减少，其机制尚不清楚。因此，我们的中心假设是F508-CFTR的短尖顶膜半衰期是由于F508-CFTR在顶膜转运的调节改变所致。我们的具体目标是： 1.验证F508-CFTR的短顶膜半衰期是细胞吞噬作用加速或细胞内循环减弱或两者兼而有之的假说。 2.阐明促进wt-CFtR和F508-cftr在根尖膜转运的接头蛋白复合体。 3.确定接头蛋白复合体调节wt-CFTR和F508-CFTR在根尖膜转运的机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mutations in the CFTR gene are responsible for cystic fibrosis (CF). The most common mutation, F508 inhibits CFTR biogenesis and leads to the absence of CFTR at the plasma membrane. When F508-CFTR is allowed to traffic to the apical plasma membrane, it is partially functional as a Cl- channel. Thus, restoration of the apical membrane expression of F508-CFTR is a potential therapeutic approach for CF, currently under investigation by several research laboratories. However, the apical membrane half-life of F508-CFTR is reduced and the mechanism remains unknown. Thus, our central hypothesis is that the short apical membrane half-life of F508-CFTR results from altered regulation of F508-CFTR trafficking at the apical membrane. Our specific aims are: 1. To test the hypothesis that the short apical membrane half-life of F508-CFTR results from either accelerated endocytosis or attenuated endocytic recycling or both. 2. To elucidate the adaptor protein complexes that facilitate trafficking of wt-CFTR and F508-CFTR at the apical membrane. 3. To identify the mechanisms by which the adaptor protein complexes regulate trafficking of wt-CFTR and F508-CFTR at the apical membrane.