Understanding the elusive mechanism of action of TCF7L2 in metabolism.
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ABSTRACT:
SUBMITTER: Grant SF
PROVIDER: S-EPMC3478546 | biostudies-literature | 2012 Nov
REPOSITORIES: biostudies-literature
Publications
Understanding the elusive mechanism of action of TCF7L2 in metabolism.
Diabetes 20121101 11
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Project description:Although praziquantel (PZQ) has been used to treat schistosomiasis for over 20 years its mechanism of action remains unknown. We have developed an assay based on the transcriptional response of S. mansoni PR-1 to heat shock to confirm that while 6 week post infection (p.i.) schistosomes are sensitive to PZQ, 4 week p.i. schistosomes are not. Further, we have used this assay to demonstrate that this sensitivity develops between days 37 and 40 p.i. PZQ linked to the fluorophore BODIPY appears to easily enter the cells of intact 4 and 6 week p.i. schistosomes as well as mammalian NIH 3T3 cells and together, these data suggest that the differential effects of PZQ is not based on cell exclusion but probably due the differential expression of a target molecule at 6 weeks p.i. A transcriptomal analysis of gene expression between 4 and 6 weeks p.i. revealed 607 candidate genes whose products are potential PZQ targets. A comparison of this gene list with that of genes expressed by PZQ sensitive miracidia reduced this target list to 247 genes, including a number involved in aerobic metabolism and cytosolic calcium regulation. Finally, we also report the effect of an in vitro sub-lethal exposure of PZQ on the transcriptome of S. mansoni PR-1. Annotation of genes differentially regulated by PZQ exposure suggests that schistosomes may undergo a transcriptomic response similar to that observed during oxidative stress. Keywords: cell type comparison, time course Cell type comparison: Four biologial replactes of schistosomes harvasted 4 and 6 week post-infection were performed. Time course: Four samples performed in duplicate for exposure to a sub-lethal dose of PZQ (50 M-BM-5g/ml) at time points 0, 30, 60, and 240 min over a common reference sample.
2008-11-10 | E-GEOD-12850 | biostudies-arrayexpress
Project description:Although praziquantel (PZQ) has been used to treat schistosomiasis for over 20 years its mechanism of action remains unknown. We have developed an assay based on the transcriptional response of S. mansoni PR-1 to heat shock to confirm that while 6 week post infection (p.i.) schistosomes are sensitive to PZQ, 4 week p.i. schistosomes are not. Further, we have used this assay to demonstrate that this sensitivity develops between days 37 and 40 p.i. PZQ linked to the fluorophore BODIPY appears to easily enter the cells of intact 4 and 6 week p.i. schistosomes as well as mammalian NIH 3T3 cells and together, these data suggest that the differential effects of PZQ is not based on cell exclusion but probably due the differential expression of a target molecule at 6 weeks p.i. A transcriptomal analysis of gene expression between 4 and 6 weeks p.i. revealed 607 candidate genes whose products are potential PZQ targets. A comparison of this gene list with that of genes expressed by PZQ sensitive miracidia reduced this target list to 247 genes, including a number involved in aerobic metabolism and cytosolic calcium regulation. Finally, we also report the effect of an in vitro sub-lethal exposure of PZQ on the transcriptome of S. mansoni PR-1. Annotation of genes differentially regulated by PZQ exposure suggests that schistosomes may undergo a transcriptomic response similar to that observed during oxidative stress. Keywords: cell type comparison, time course
2008-11-10 | GSE12850 | GEO
Project description:Although praziquantel (PZQ) has been used to treat schistosomiasis for over 20 years its mechanism of action remains unknown. We have developed an assay based on the transcriptional response of Schistosoma mansoni PR-1 to heat shock to confirm that while 6-week post-infection (p.i.) schistosomes are sensitive to PZQ, 4-week p.i. schistosomes are not. Further, we have used this assay to demonstrate that in mice this sensitivity develops between days 37 and 40 p.i. When PZQ is linked to the fluorophore BODIPY to aid microscopic visualization, it appears to enter the cells of intact 4 and 6-week p.i. schistosomes as well as mammalian NIH 3T3 cells with ease suggesting that the differential effects of PZQ is not based on cell exclusion. A transcriptomal analysis of gene expression between 4 and 6 weeks p.i. revealed 607 up-regulated candidate genes whose products are potential PZQ targets. A comparison of this gene list with that of genes expressed by PZQ sensitive miracidia reduced this target list to 247 genes, including a number involved in aerobic metabolism and cytosolic calcium regulation. Finally, we also report the effect of an in vitro sub-lethal exposure of PZQ on the transcriptome of S. mansoni PR-1. Annotation of genes differentially regulated by PZQ exposure suggests that schistosomes may undergo a transcriptomic response similar to that observed during oxidative stress.
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Project description:1,25-Dihydroxvitamin D3 [1,25(OH)2D3] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH)2D3 action involves the direct binding of the 1,25(OH)2D3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH)2D3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH)2D3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.
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