Erythrocyte Raft Signaling In Malarial Infection

描述(申请人提供)：疟疾是一种主要的传染病。保守估计，每年有200-3亿人受到这种疾病的困扰，超过100万儿童死于这种感染。恶性疟原虫是人类疟疾中最致命的一种。恶性疟原虫的一个显著特征是感染成熟的红细胞。尽管这是一个非内吞的宿主细胞，但其信号蛋白如异源三聚体Gs和G蛋白偶联受体(GPCRs)调节恶性疟原虫的感染。这个项目的总体目标是详细了解恶性疟原虫和疟疾寄生虫在红细胞中诱导信号的分子和细胞机制。预计这项研究将有助于理解通过红细胞异源三聚体Gs蛋白传递的信号如何增加疟疾感染和病理的易感性，从而有助于了解寄生虫和疾病的基本生物学。将使用分子、微生物遗传工具、功能基因组学结合高分辨率成像技术、生化分析以及血液学和宿主遗传学方面的专业知识来研究导致空泡形成的机制，改变宿主红细胞膜的基本属性，并增强对疟疾的抵抗力。在这些研究中收集的信息可能对理解制定抗疟疾感染和溶血性疾病治疗策略的机制很重要。

DESCRIPTION (provided by applicant): Malaria is a major infectious disease. Conservative estimates predict that 2-300 million people are afflicted and over a million children die from the infection each year. Plasmodium falciparum causes the most virulent form of human malaria. A striking feature of P. falciparum is its infection of the mature erythrocyte. Despite the fact that this is a non-endocytic host cell, its signaling protein such as the heterotrimeric Gs and G protein coupled receptors (GPCRs) regulate infection of P. falciparum. The overall objective of this project is to develop a detailed understanding of the molecular and cellular mechanisms by which P. falciparum and malaria parasites induce signaling in erythrocytes. It is anticipated that study will lead to understanding how signaling via the erythrocyte heterotrimeric Gs protein confers susceptibility to malarial infection and pathology and thereby contribute to understanding the basic biology of the parasite as well as disease. Molecular, microbial genetic tools using transfection, functional genomics combined with high resolution imaging techniques, biochemical assays as well as expertise in hematology and host genetics, will be used to investigate mechanisms that lead to vacuole formation, modify basic membrane properties of the host erythrocyte and confer resistance against malaria. The information gathered in these studies may be important to understanding mechanisms that underlie development of therapeutic strategies against malarial infection and hemolytic disorders.