Immune modualtion of schistosome development

描述（由申请人提供）：全球至少有 20 亿人遭受蠕虫感染，其中大多数居住在发展中国家。蠕虫与病毒、细菌和原生生物的不同之处在于，它们表现出复杂的生命周期，通常涉及多种发育途径，从而导致不同的表型结果。发育决策被认为受到宿主因素的影响，并为寄生虫提供了一种应对宿主体内不断变化的条件的方法。该提案的主要目标是利用血吸虫感染的小鼠模型，对参与这些相互作用的信号和受体进行分子理解。这些知识应该揭示破坏蠕虫生命周期以达到治疗和预防目的的新机会。 血吸虫属吸虫影响着全世界 2 亿人，构成了致病性蠕虫的有用且重要的实验室模型。涉及曼氏链霉菌的研究表明，哺乳动物宿主内正常发育的启动取决于寄生虫接收到适当的宿主信号。肝脏 CD4 T 细胞在向发育中的蠕虫传递该信号方面发挥着核心作用。此外，CD4 T 细胞和发育中的血吸虫之间发生密切的物理相互作用。该提案的具体目标 1 是确定负责调节血吸虫发育的宿主分子。将使用阵列技术和支持分子技术系统地鉴定肝 CD4 T 细胞产生的候选分子。然后，将使用基因改造的小鼠在体内测试合适的候选物的调节活性，并使用正在开发的寄生虫培养系统在体外测试合适的候选物的调节活性。具体目标 2 提出通过采用信号序列陷阱库筛选方法来鉴定参与与 CD4 T 细胞物理相互作用的血吸虫分子。具体目标3是确定基因转录的分子差异，这些差异是来自野生型小鼠的正常寄生虫和来自免疫缺陷动物的减毒寄生虫之间明显表型差异的基础。这一具体目标将利用新兴的阵列技术和支持分子技术来识别在寄生虫的两种表型状态下差异表达的基因。鉴定出的基因将为寄生虫发育提供有价值的分子标记，以供后续研究使用。

DESCRIPTION (provided by applicant): At least two billion people suffer from helminth infections globally, the majority of whom reside in the developing world. Helminths differ from viruses, bacteria and protists in that they exhibit complex life cycles, often involving multiple developmental pathways that result in different phenotypic outcomes. Developmental decisions are believed to be influenced by host factors and provide the parasite with a means to respond to changing conditions within the host. The broad objectives of this proposal are to develop a molecular understanding of the signals and receptors involved in these interactions, using a murine model of schistosome infection. This knowledge should reveal new opportunities to disrupt helminth life cycles for therapeutic and prophylactic purposes. Trematodes of the genus Schistosoma, which affect 200 million people worldwide, constitute a useful and important laboratory model of pathogenic helminths. Studies involving S. mansoni have demonstrated that initiation of normal development within the mammalian host is dependent on the receipt of appropriate host signals by the parasite. Hepatic CD4+ T cells play a central role in delivering this signals to the developing worm. Further, an intimate physical interaction occurs between CD4+ T cells and developing schistosomes. Specific aim 1 of this proposal it to identify the host molecules responsible for modulating schistosome development. Candidate molecules produced by hepatic CD4+ T cells will be systematically identified using array technology and supporting molecular techniques. Suitable candidates will then be tested for modulatory activity in vivo, using genetically altered mice, and in vitro, using a developing parasite culture system. Specific aim 2 proposes to identify schistosome molecules that participate in the physical interaction with CD4+ T cells by employing a signal sequence trap library screening approach. Specific aim 3 is to identify the molecular differences in gene transcription that underlie the obvious phenotypic differences between normal parasites from wild type mice and attenuated parasites from immunodeficient animals. This specific aim will make use of emerging array technology and supporting molecular techniques to identify genes that are differentially expressed in the two phenotypic states of the parasite. Identified genes will provide valuable molecular markers of parasite development for use in subsequent studies.