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.
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