Structure and Function of E. histolytica Adherence Lectin

描述（由申请方提供）：阿米巴性结肠炎和肝脓肿是由于肠道原生动物寄生虫溶组织内阿米巴感染所致。世界卫生组织估计，全世界每年约有5000万人遭受侵袭性阿米巴感染。E.溶组织原虫滋养体通过半乳糖结合（Gal/GalNAc）凝集素结合到肠粘蛋白和上皮细胞是寄生虫杀死宿主细胞和侵入所必需的。我们发现这种凝集素的中间亚基是E. 80多种跨膜激酶（TMK）的溶组织基因家族。TMK激酶结构域是新颖的，并且TMK的数量在单细胞生物体中是前所未有的。我们假设TMKs是一个主要的受体系统，用于感知环境和控制寄生虫的入侵行为。我们拟检测TMK是否发生抗原变异，确定TMK 96是否为双特异性（tyr和ser/thr）激酶，并鉴定其下游效应子和调节子，研究TMK 96调节的生物学活性。我们将重点关注TMK 96在凋亡尸体的粘附，杀伤和内吞作用中的作用，因为它已被确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类肠道的手段。

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.