Mechanisms of Erythrocytic Infection & Anemia in Malaria

描述（由申请人提供）： 该计划的总体目标是详细了解疟原虫感染红细胞并诱导哺乳动物宿主贫血的分子和细胞机制。 预计拟议的研究将导致了解寄生虫蛋白及其复合物如何与宿主受体和信号传导途径相互作用，以介导（i）红细胞中感染的建立以及（ii）外周循环中未感染红细胞的清除和与疟疾贫血相关的无效红细胞生成。 为了实现这些目标，提出了三个互补的项目，协同在上级水平。1)确定是否通过红细胞筏相关的Gs和寄生虫配体，在寄生虫进入成核信号筏复合物的信号传递赋予疟疾感染的易感性，并改变红细胞膜的特性。 2)研究人类疟疾感染和疟疾小鼠模型中红细胞粘附和红细胞生成障碍的寄生虫蛋白及其复合物。3)建立非人类灵长类动物贫血模型，以测试从小鼠模型获得的机制见解，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，一组具有血液学，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，啮齿动物和非人灵长类动物模型专业知识的研究人员聚集在一起，共同努力。在这些研究中收集的信息有望导致疟疾感染和贫血的治疗策略的发展。

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.