The role of the N-methyl-D-aspartate receptor in heart development: A gene knockdown model using siRNA. Octavian V Lie

ISBN: 9781109193084

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NOOKstudy eTextbook

177 pages


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The role of the N-methyl-D-aspartate receptor in heart development: A gene knockdown model using siRNA.  by  Octavian V Lie

The role of the N-methyl-D-aspartate receptor in heart development: A gene knockdown model using siRNA. by Octavian V Lie
| NOOKstudy eTextbook | PDF, EPUB, FB2, DjVu, talking book, mp3, ZIP | 177 pages | ISBN: 9781109193084 | 6.49 Mb

The exploration of the interplay between environment and genetics leading to congenital heart defects has gained momentum with the realization that the accumulation of homocysteine, whether or not secondary to deficient folate, increases the risk ofMoreThe exploration of the interplay between environment and genetics leading to congenital heart defects has gained momentum with the realization that the accumulation of homocysteine, whether or not secondary to deficient folate, increases the risk of heart defects. Studies conducted in the chicken embryo have suggested that central to homocysteine teratogenesis was its interference with the cardiac neural crest, a migratory cell population that contributes to key aspects of cardiogenesis.

With the demonstration that homocysteine is an NMDA receptor antagonist, it was postulated that the inhibition of the NMDA receptor impairs normal cardiac development by interference with cardiac neural crest homeostasis. Support for this hypothesis has been largely provided by epidemiological and experimental pharmacological studies. The project detailed herein was designed to test this hypothesis at the molecular level, leading to the cardiac phenotyping of a chicken NMDA receptor loss-of-function model created by the restricted knockdown of the critical subunit NR1. A first set of experiments generated the full coding sequence of the chicken NR1.

The analysis of the temporal NR1 mRNA expression by RT-PCR demonstrated the presence of a single NR1 isoform species starting with the premigratory crest stages. The spatial NR1 expression was demonstrated by in situ hybridization to be concentrated largely within the neural tube, the site of the premigratory crest.

Next, a restricted transgenic chicken model was created by the bilateral neural tube transfection of small interfering RNAs targeting NR1 using in ovo electroporation, a revolutionary technique adapted in this study for the long-term labeling of cardiac neural crest. The chicken NR1 knockdown model was characterized on average by a 35% decrease in the NR1 protein at the neural tube level generating cardiac neural crest. The analysis of the embryo survival and congenital heart defect rates associated with NR1 knockdown does not support a direct involvement of the NMDA receptor in the genesis of cardiac neural crest-related congenital heart defects.



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