The long-term goal of the proposed research is to identify and functionally characterize the genes regulating intramolluscan larval development in the human blood fluke Schistosoma mansoni. Schistosome development within the snail intermediate host is complex, involving several stages including the snail-infective miracidium, mother sporocyst, daughter sporocyst, and finally the human-infective cercaria. Because the miracidium -to-mother sporocyst transition is assumed to involve numerous physiological adaptations going from its free-living to parasitic existence, it is hypothesized that such a transition is regulated by critical, stage-specific changes in gene expression. Similarly, the initiation of asexual reproduction (embryogenesis) in mother sporocysts to give rise to multiple daughter sporocysts and within daughters, the formation of cercariae, is presumed to involve developmental processes orchestrated through the differential expression of genes in a stage-specific fashion. However, to date, very little is known regarding the identity of genes expressed in molluscan larval stages, especially the asexually reproducing sporocysts, and there exists no information on changes in gene expression profiles associated with sequential development from the miracidium to mother sporocyst to daughter sporocyst stages. To address this critical information gap, and to begin investigating the hypothesis that larval development is driven by defined stage-specific changes in gene expression, the following specific aims are proposed: (1) to evaluate gene expression profiles for miracidia and mother sporocysts (early-and late-developing) under in vitro culture conditions by employing S. mansoni oligonucleotide gene microarrays;(2) to confirm and validate in vitro DNA microarray results by measuring expression of specific genes in mother sporocysts developing under in vivo infections conditions;(3) to investigate the effects of snail host factors on larval schistosome gene expression using schistosome gene microarray analyses, followed by identification and characterization of larval expression-modulating snail molecules;and (4) to evaluate whether specific genes found to be upregulated in a larval stage-associated manner are functionally tied to defined developmental phenotypes using double-stranded RNA interference methods. It is anticipated that the proposed microarray profiling approach will fill a critical information gap regarding S. mansoni larval stage-associated gene expression, and will provide important insights into the role of specific genes in regulating the developmental process. Results of this work may lead to novel strategies for controlling infections within the snail host by disrupting specific larval development-dependent genes or their products.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI061436-05
Application #
7544963
Study Section
Special Emphasis Panel (ZRG1-VB (01))
Program Officer
Joy, Deirdre A
Project Start
2005-04-01
Project End
2010-12-31
Budget Start
2009-01-01
Budget End
2010-12-31
Support Year
5
Fiscal Year
2009
Total Cost
$335,748
Indirect Cost
Name
University of Wisconsin Madison
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Peterson, Nathan A; Anderson, Tavis K; Yoshino, Timothy P (2013) In silico analysis of the fucosylation-associated genome of the human blood fluke Schistosoma mansoni: cloning and characterization of the fucosyltransferase multigene family. PLoS One 8:e63299
Soares, Cláudia Sossai; Morais, Enyara Rezende; Magalhães, Lizandra G et al. (2013) Molecular and functional characterization of a putative PA28? proteasome activator orthologue in Schistosoma mansoni. Mol Biochem Parasitol 189:14-25
Peterson, Nathan A; Anderson, Tavis K; Wu, Xiao-Jun et al. (2013) In silico analysis of the fucosylation-associated genome of the human blood fluke Schistosoma mansoni: cloning and characterization of the enzymes involved in GDP-L-fucose synthesis and Golgi import. Parasit Vectors 6:201
Taft, Andrew S; Yoshino, Timothy P (2011) Cloning and functional characterization of two calmodulin genes during larval development in the parasitic flatworm Schistosoma mansoni. J Parasitol 97:72-81
Yoshino, Timothy P; Dinguirard, Nathalie; Mourão, Marina de Moraes (2010) In vitro manipulation of gene expression in larval Schistosoma: a model for postgenomic approaches in Trematoda. Parasitology 137:463-83
Taft, Andrew S; Norante, Francesca A; Yoshino, Timothy P (2010) The identification of inhibitors of Schistosoma mansoni miracidial transformation by incorporating a medium-throughput small-molecule screen. Exp Parasitol 125:84-94
Taft, A S; Vermeire, J J; Bernier, J et al. (2009) Transcriptome analysis of Schistosoma mansoni larval development using serial analysis of gene expression (SAGE). Parasitology 136:469-85
Mourão, M M; de Moraes Mourão, Marina; Dinguirard, Nathalie et al. (2009) Phenotypic screen of early-developing larvae of the blood fluke, schistosoma mansoni, using RNA interference. PLoS Negl Trop Dis 3:e502
Peterson, Nathan A; Hokke, Cornelis H; Deelder, André M et al. (2009) Glycotope analysis in miracidia and primary sporocysts of Schistosoma mansoni: differential expression during the miracidium-to-sporocyst transformation. Int J Parasitol 39:1331-44
Fitzpatrick, Jennifer M; Peak, Emily; Perally, Samirah et al. (2009) Anti-schistosomal intervention targets identified by lifecycle transcriptomic analyses. PLoS Negl Trop Dis 3:e543

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