Developmental Gene Regulation in Schistosoma mansoni

描述（由申请方提供）：血吸虫病是一种重要的热带寄生虫病，在70多个国家有2亿多人感染。在撒哈拉以南非洲，由于艾滋病毒感染造成的死亡率估计为每年28万人，另有2 000万人患有严重的疾病症状。目前，药物治疗是基于一个单一的代理，吡喹酮，并有证据支持抗药性寄生虫的出现。由于没有合适的替代疗法或疫苗可用，因此迫切需要开发新的化疗剂和疫苗。更多关于核糖体基础生物学的详细信息将有助于疫苗和新药的设计。我们认为，确定控制蠕虫的发展和性分化的哺乳动物宿主的因素将提供新的药物和疫苗的目标。在哺乳动物宿主发育过程中，对蠕虫全基因组基因表达模式的研究将为影响寄生虫适应宿主环境的生物学途径提供一幅连贯的图景。我们建议利用基因表达系列分析（SAGE）来监测寄生虫发育和性别分化过程中mRNA表达的全基因组水平。为了检测与发育相关的基因的差异转录，我们将通过从从尾蚴、童虫、未成熟蠕虫、性成熟和处女蠕虫以及卵分离的mRNA产生约75，000个20 bp序列标签来进行SAGE。SAGE是研究寄生虫发育和性别分化过程中基因表达的理想工具。这项研究将导致识别在发育和性分化过程中表达的新基因，这些基因允许寄生虫逃避免疫反应并在哺乳动物宿主中持续存在。随着曼氏血吸虫基因组测序的接近完成，功能基因组研究将是必不可少的，以利用正在产生的大规模基因组数据库。SAGE分析将补充正在进行的S. mansoni基因组和使用DNA微阵列的研究。此外，我们将验证使用SAGE技术研究差异的整体基因表达在S。mansoni

DESCRIPTION (provided by the applicant): Schistosomiasis is an important tropical parasitic disease with more than two hundred million human infections in more than 70 countries. The mortality due to schistosome infections in sub-Saharan Africa is estimated to be 280,000 per year and an additional 20 million individuals suffer severe disease symptoms. Currently, drug treatment is based on a single agent, praziquantel, and there is evidence supporting the emergence of drug resistant parasites. Because no suitable alternative therapy or vaccine is available, there is an urgent need for the development of novel chemotherapeutic agents and vaccines. More detailed information about the basic biology of schistosomes will facilitate vaccine and novel drug design. We suggest that identification of factors controlling worm development and sexual differentiation in the mammalian host will provide new targets for drugs and vaccines. Examination of genome-wide gene expression patterns in worms during development in the mammalian host will provide a coherent picture of schistosome biological pathways that influence parasite adaptation to the host environment. We propose to utilize Serial Analysis of Gene Expression (SAGE) to monitor genome-wide levels of mRNA expression during parasite development and sexual differentiation. To detect differential transcription of genes related to development, we will perform SAGE by generating ~75,000 20 bp sequence tags from the mRNA isolated from cercariae, schistosomula, immature worms, sexually mature and virgin worms, and eggs. SAGE is ideal to investigate global gene expression during parasite development and sexual differentiation. This research will lead to the identification of novel genes expressed during development and sexual differentiation and that allow the parasite to evade the immune response and persist in the mammalian host. As genome sequencing of Schistosoma mansoni is nearly complete, functional genomic studies will be essential to capitalize on the massive genomic database being generated. SAGE analysis will complement the ongoing annotation of the S. mansoni genome and studies using DNA micro arrays. Furthermore, we will validate the use of SAGE technology to study differential global gene expression in S. mansoni.