SIGNAL TRANSDUCTION IN SCHISTOSOMES

我们的研究目标是了解信号转导途径如何调节染色体发育。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来响应来自环境的刺激。我们建议研究两个信号通路，我们有生物学相关的信息。(l)TGF β途径，其表面暴露受体已被鉴定（TbetaRI），因此意味着它被寄生虫用于接收来自宿主环境的信号。(2)雄性用来刺激雌性基因表达，调节雌性生殖发育和产卵的途径。对于后者，我们已经证明了核受体亚家族RXR的成员在女性特异性基因表达中发挥作用。具体目标是：（1）确定和表征参与女性特异性基因表达的调控蛋白。最终的目标是确定男性刺激，调节女性特异性基因表达。为此，我们已经确定了令人讨厌的RXR家族的成员。一个成员，SmRXR 1，本身就足以结合到一个顺式元件和激活转录的女性特异性基因（p14）。因此，我们已经确定了一个候选成员的终点途径。我们建议使用两种策略来识别女性特异性基因调节途径的其他组成部分，并向后努力识别男性信号。(a)鉴定与模型雌性特异性基因p14的顺式元件结合的其它反式作用因子。（B）使用SmRXR 1鉴定参与p14基因表达调控的潜在配偶体和配体。在（a）和（B）中，我们将确定确定的相互作用是否在体外响应雄性和雌性交配时发生。（2）探讨TGF β（Ser/Thr kinase）通路在哺乳动物宿主-溶酶体相互作用中的生物学意义。丝氨酸/苏氨酸激酶受体已被鉴定为暴露于脊椎动物阶段的S. mansoni这表明ser/thr激酶通路在接收来自宿主环境的信号中一定很重要。因此，我们将：（a）鉴定溶酶体TGF β途径的成员（B）建立并使用替代系统来评估溶酶体TGF β途径组分的功能。(c)评估在染色体-宿主相互作用中，染色体TGF β通路组分的功能。我们的研究工作旨在了解信号转导在雌雄寄生虫相互作用以及寄生虫与其宿主环境相互作用中的作用。我们希望确定有用的目标，控制寄生虫的发展和/或寄生虫引起的发病率。

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.