SIGNAL TRANSDUCTION IN SCHISTOSOMES

我们的研究目标是了解信号转导途径如何调节血吸虫的发育。信号转导途径将信息从寄生虫表面传递到各种细胞的细胞核，这使得细胞能够通过基因表达的变化对环境的刺激做出反应。我们建议研究两种信号通路，我们有生物学相关的信息。(l) tgf β通路，其表面暴露受体（TbetaRI）已被鉴定，因此表明寄生虫利用它来接收来自宿主环境的信号。(2)雄性刺激雌性基因表达，调控雌性生殖发育和产卵的途径。对于后者，我们已经证明核受体亚家族RXR的成员在女性特异性基因表达中发挥作用。具体目的是：(1)识别和表征参与女性特异性基因表达的调节蛋白。最终目标是确定调节雌性特定基因表达的雄性刺激。为此，我们确定了血吸虫RXR家族的成员。其中一个成员SmRXR1本身就足以结合顺式元件并激活女性特异性基因的转录（p14）。因此，我们在该通路的末端确定了一个候选成员。我们建议使用两种策略来识别女性特异性基因调控途径的其他组成部分，并反向工作以识别男性信号。(a)确定与典型女性特异性基因p14的顺式元件结合的其他交易因子。(b)利用SmRXR1识别参与pl4基因表达调控的潜在伴侣和配体。在(a)和(b)中，我们将确定确定的相互作用是否在体外对雄性和雌性交配作出反应。(2)评价TGFbeta （Ser/Thr kinase）通路在血吸虫与哺乳动物宿主相互作用中的生物学意义。一个丝氨酸/苏氨酸激酶受体已被确定为表面暴露在曼陀罗的脊椎动物阶段。这表明丝氨酸/苏氨酸激酶途径在接收来自宿主环境的信号中一定很重要。因此，我们将：(a)鉴定血吸虫tgf β途径的成员(b)建立并使用替代系统来评估血吸虫tgf β途径组分的功能。(c)评价血吸虫tgf β途径组分在血吸虫-宿主相互作用中的作用。我们的研究工作旨在了解信号转导在雄性和雌性寄生虫的相互作用以及寄生虫与宿主环境的相互作用中的作用。我们期望找到控制寄生虫发育和/或寄生虫引起的发病率的有用靶点。

Our research goal is to understand how signal transduction pathways regulate schistosome development. Signal transduction pathways convey information from the parasite surface to the nucleus of various cells and this enables the cells to respond to stimuli from the environment by changes in gene expression. We propose to study two signaling pathways for which we have biologically relevant information. (l) The TGFbeta pathway for which a surface exposed receptor has been identified (TbetaRI) and thus implies that it is used by the parasite to receive signals from the host environment. (2) The pathway employed by the male to stimulate female gene expression that regulates female reproductive development and egg production. For the later we have demonstrated that members of the nuclear receptor subfamily RXR play a role in female-specific gene expression. The specific aims are to: (l) identify and characterize regulatory proteins involved in female-specific gene expression. The ultimate goal is to identify the male stimulus that regulates female-specific gene expression. To that end we have identified members of the schistosome RXR family. One member, SmRXR1, by itself is sufficient to bind to a cis element and activate transcription of a female-specific gene (p14). Thus we have identified a candidate member at the terminus of the pathway. We propose to use two strategies to identify other components of the female-specific gene regulation pathway and work backward towards identifying the male signal. (a) identify additional transacting factors that bind to the cis-elements of a model female-specific gene, p14. (b)Use SmRXR1 to identify potential partners and ligands involved in regulation of pl4 gene expression. In (a) and (b) we will determine whether the identified interactions occur in vitro in response to male and female mating. And (2) Evaluate the biological significance of TGFbeta (Ser/Thr kinase) pathway in schistosome-mammalian host interactions. A Ser/Thr kinase receptor has been identified to be surface exposed on vertebrate stages of S. mansoni. This argues that the ser/thr kinase pathway must be important in receiving signals from the host environment. Therefore we will: (a) identify members of schistosome TGFbeta pathway (b) Establish and employ surrogate systems to evaluate the function of the components of the schistosome TGFbeta pathway. (c) Evaluate the function of the components of the schistosome TGFbeta pathway in schistosome-host interactions. Our research effort is aimed at understanding the role of signal transduction in the interaction of the male and female parasites and the interaction of the parasite with its host environment. We expect to identify useful targets for control of parasite development and/or parasite caused morbidity.