Immune modualtion of schistosome development

描述（由申请人提供）：全球至少有20亿人患有蠕虫感染，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，通常涉及导致不同表型结果的多种发育途径。发育决定被认为是受宿主因素的影响，并为寄生虫提供了一种手段，以应对宿主内不断变化的条件。这个建议的广泛目标是发展一个分子的理解，在这些相互作用中涉及的信号和受体，使用小鼠模型的染色体感染。这些知识应该揭示出于治疗和预防目的扰乱蠕虫生命周期的新机会。 血吸虫属的吸虫在全世界影响2亿人，构成了致病性蠕虫的有用和重要的实验室模型。研究涉及S. mansoni等人已经证明，哺乳动物宿主内正常发育的启动依赖于寄生虫接收适当的宿主信号。肝脏CD4+ T细胞在将这些信号传递给发育中的蠕虫中起着核心作用。此外，在CD4+ T细胞和发育中的溶酶体之间发生密切的物理相互作用。本提案的具体目标1是鉴定负责调节染色体发育的宿主分子。将使用阵列技术和支持分子技术系统地鉴定由肝CD4+ T细胞产生的候选分子。然后使用遗传改变的小鼠在体内和使用发育中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文库筛选方法来鉴定参与与CD4+ T细胞的物理相互作用的溶酶体分子。具体目标3是确定基因转录的分子差异，这些差异是野生型小鼠的正常寄生虫和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，以确定在寄生虫的两种表型状态下差异表达的基因。所鉴定的基因将为后续研究提供有价值的寄生虫发育分子标记。

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.