Structure and Function of E. histolytica Adherence Lectin

描述(申请人提供)：阿米巴结肠炎和肝脓肿是由肠道原虫寄生虫组织溶解内阿米巴感染引起的。世界卫生组织估计，全球每年约有5000万人遭受侵袭性阿米巴感染。半乳糖结合(Gal/GalNAc)凝集素使溶组织棘球绦虫与肠粘蛋白和肠上皮细胞黏附，是其杀灭宿主细胞和入侵所必需的。我们已经发现该凝集素的中间亚单位是一个由80多个跨膜蛋白激酶(TMK)组成的溶组埃希菌基因家族的一部分。TMK激酶结构域是新的，在单细胞生物体中TMK的数量是前所未有的。我们推测TMKs是感知环境和控制寄生虫入侵行为的主要受体系统。我们建议测试TMK是否经历抗原变异，确定TMK 96是否是双特异性(Tyr和Ser/Thr)激酶，并确定其下游效应和调节因子，并研究TMK 96调节的生物活性。我们将重点介绍TMK 96在凋亡身体的黏附、杀伤和内吞中的作用，因为它已经被鉴定为吞噬体蛋白质组的一部分。这些研究的成功完成将提供有关这些新型受体激酶的基础知识，并深入了解寄生虫控制其入侵人体肠道的方式。

DESCRIPTION (provided by applicant): Amebic colitis and liver abscess are due to infection with the enteric protozoan parasite Entamoeba histolytica. The World Health Organization estimates that approximately 50 million people worldwide suffer from invasive amebic infection each year. The adherence of E. histolytica trophozoites to intestinal mucins and epithelial cells by a galactose-binding (Gal/GalNAc) lectin is necessary for the parasite to kill host cells and invade. We have discovered that the intermediate subunit of this lectin is part of an E. histolytica gene family of more than 80 transmembrane kinases (TMK). The TMK kinase domains are novel and the number of TMKs is unprecedented in a unicellular organism. We hypothesize that the TMKs are a major receptor system for sensing the environment and controlling the invasive behavior of the parasite. We propose to test if the TMKs undergo antigenic variation, determine if TMK 96 is a dual specificity (tyr and ser/thr) kinase and identify its downstream effectors and regulators, and study the biologic activities regulated by TMK 96. We will focus on the role of TMK 96 in the adherence, killing and endocytosis of apoptotic corpses as it has been identified as part the phagosome proteome. Successful completion of these studies will provide fundamental knowledge of these novel receptor kinases and insight into the means by which the parasite controls its invasion into the human intestine.