Comparative omics analyses of cellular invasion by Plasmodium sporozoites

项目摘要 这一系列研究的长期目标是通过改进来确定疟疾疫苗的新靶点。 了解引起这种疾病的寄生虫--疟原虫对细胞的入侵。这项研究还将 关注寄生虫的感染阶段，即子孢子，它有一个复杂的旅程，尽管 蚊子和人体。我们在这个项目中的总体目标是确定 疟原虫与两种截然不同的宿主组织--蚊子唾液腺组织和蚊子唾液腺组织的相互作用 人类的肝脏。确定与疟原虫细胞入侵有关的新因素将使 确定新的疫苗靶点，用于未来的转译研究。我们的中心假设是 疟原虫子孢子需要涉及宿主细胞衍生的上皮因子的类似机制 蚊子唾液腺和人类肝细胞的入侵。这项研究的基本原理是 确定参与疟原虫子孢子细胞入侵的新因素将使 识别新的疫苗靶点。我们将使用啮齿动物和人类疟疾模型来验证我们的假设 解决两个具体目标。在目标1中，我们将确定特定的人类肝细胞衍生因子在 被疟原虫入侵。我们将在人类肝细胞和小鼠模型中使用基因敲除 目的探讨特异基因在疟原虫侵袭中的作用。在目标2中，我们将确定 结合糖基修饰的特定蛋白质对子孢子入侵的影响程度 蚊子的唾液腺。同样，我们将主要使用基因敲除研究与寄生虫入侵相结合。 测试几种蚊子唾液腺基因在寄生虫入侵过程中的作用的实验。这个 这项研究的结果有望确定特定的肝脏蛋白在子孢子中所起的作用。 生命周期。我们的发现的主要影响预计是确定子孢子所需的因素。 宿主细胞的入侵，是生命阶段最合乎逻辑的发展目标，也是有效和 负担得起的疟疾疫苗。

Project Summary The long-term goal of this line of research is to identify novel vaccine targets for malaria through improved understanding of cellular invasion by the parasite that causes this disease, Plasmodium. This research will also focus on the infectious stage of the parasite, the sporozoite, which has a complicated journey though both the mosquito and human body. Our overall objective in this project is to identify the precise mechanisms of interaction between Plasmodium and two contrasting host tissues, those of the mosquito salivary glands and the human liver. The determination of novel factors involved in cellular invasion by Plasmodium will allow the identification of novel vaccine targets for use in future translational studies. Our central hypothesis is that similar mechanisms involving host cell-derived epithelial factors are required for Plasmodium sporozoite invasion of both mosquito salivary glands and human hepatocytes. The rationale for this study is that determination of novel factors involved in cellular invasion by Plasmodium sporozoites will allow the identification of novel vaccine targets. We will test our hypothesis using rodent and human malaria models to address two specific Aims. In Aim 1, we will define the role of specific human liver cell-derived factors during invasion by Plasmodium. We will use gene knock-out in human liver cells and knock-out mouse models in order to investigate the effects of specific genes on Plasmodium invasion. In Aim 2, we will determine the extent to which specific proteins modified with attached sugar groups influence sporozoite invasion of the mosquito salivary glands. Again, we will primarily use gene-knock out studies combined with parasite invasion experiments to test for the involvement of several mosquito salivary gland genes during parasite invasion. The outcomes of this study are expected to be identification of the role specific liver proteins play in the sporozoite life cycle. The primary impact of our findings is anticipated to be identification of factors required for sporozoite invasion of host cells, the life-stage that is the most logical target for the development of an effective and affordable malaria vaccine.