Characterizing new nematode-specific drug targets to eliminate the reservoir for human toxocariasis

项目摘要 犬弓形虫在人类体内引起内脏和眼部幼虫迁徙。这种疾病之所以不能 被消灭是因为组织寄居的幼虫持续存在于它们耐受的动物储藏室(狗) 驱虫药的治疗，耐药机制尚不清楚。我们的假设是犬毛滴虫 幼虫通过分泌具有渗透性糖蛋白的抗寄生虫药物来逃避药物治疗(P- 糖蛋白)排出驱虫药。在本申请中，我们建议1)记录P- 犬弓形虫中糖蛋白基因的表达，2)定位表达P-糖蛋白的精确组织， 3)证明了驱虫药对P-糖蛋白活性的诱导作用，4)表征了 犬毛滴虫P-糖蛋白的药理作用，以及5)发现线虫特异性P-糖蛋白抑制剂 提高了抗寄生虫药物的性能。

Project Summary Toxocara canis causes visceral and ocular larval migrans in humans. The reason why this disease cannot be eliminated is because tissue-dwelling larvae persist in the animal reservoir (dogs) where they tolerate anthelmintic treatment, and the mechanism for drug tolerance is unknown. Our hypothesis is that T. canis larvae evade drug treatment by effluxing antiparasitic drugs with permeability glycoproteins (P- glycoproteins) that efflux anthelmintics. In this application we propose to 1) record the repertoire of P- glycoprotein gene expression in T. canis, 2) map the precise tissues where P-glycoproteins are expressed, 3) demonstrate induction of P-glycoprotein activity by anthelmintic drugs, 4) characterize the unique pharmacology of T. canis P-glycoprotein, and 5) discover nematode-specific P-glycoprotein inhibitors that enhance the performance of antiparasitic drugs.