Mechanisms of Erythrocytic Infection & Anemia in Malaria

描述(由申请人提供)： 该项目的总体目标是详细了解疟疾寄生虫感染红细胞并在哺乳动物宿主中引起贫血的分子和细胞机制。预计这项拟议的研究将有助于了解寄生虫蛋白及其复合体如何与宿主受体和信号通路相互作用，以调节(I)红细胞感染的建立以及(Ii)未感染的红细胞在外周循环中的清除以及与疟疾贫血相关的无效红细胞生成。为实现这些目标，提出了三个在更高级别上协同增效的补充项目。1)确定通过红细胞筏相关的Gs和寄生虫配体在寄生虫进入期间使信号筏复合体成核的信号是否增加了对疟疾感染的易感性并改变了红细胞膜的性质。2)研究人疟原虫感染和小鼠疟疾模型红细胞黏附和红细胞生成异常中的寄生虫蛋白及其复合体。3)建立非人类灵长类动物的贫血模型，以测试从小鼠模型中获得的机械性见解，并开发和测试与人类疟疾相关的贫血的见解。为了实现这些目标，一群在血液学、寄生虫学、细胞生物学、生物化学、分子生物学、免疫学、寄生虫遗传学、功能基因组学、啮齿动物和非人类灵长类动物模型方面具有专业知识的研究人员聚集在一起，共同努力。预计在这些研究中收集的信息将有助于制定防治疟疾感染和贫血的治疗战略。

DESCRIPTION (provided by applicant): The overall objective of this program is to develop a detailed understanding of the molecular and cellular mechanisms by which malaria parasites infect erythrocytes and induce anemia in their mammalian hosts. It is anticipated that the proposed study will lead to understanding how parasite proteins and their complexes interact with host receptors and signaling pathways to mediate (i) the establishment of infection in erythrocytes as well as (ii) clearance of uninfected erythrocytes in the peripheral circulation and ineffective erythropoiesis associated with malarial anemia. To achieve these goals three complementary projects that synergize at a superior level are proposed. 1) Determine whether signaling via erythrocyte raft associated Gs and parasite ligands that nucleate signaling raft complexes during parasite entry confer susceptibility to malarial infection and alter erythrocyte membrane properties. 2) Investigate parasite proteins and their complexes in erythrocyte adhesion and dyserythropoiesis in human malaria infections and murine models of malaria. 3) Establish non-human primate models of anemia to test mechanistic insights obtained from murine models, and develop and test insights for anemia associated with human malaria. To achieve these objectives a group of investigators with expertise in hematology, parasitology, cell biology, biochemistry, molecular biology, immunology, parasite genetics, functional genomics, rodent and non-human primate models have come together to mount a concerted effort. The information gathered in these studies is expected to lead to the development of therapeutic strategies against malarial infection and anemia.