We propose to continue a multidisciplinary approach to understand the mechanism of RNA-triggered gene silencing in a model animal system, the nematode Caenorhabditis elegans.
The specific aims of the proposed research are: ? ? Characterize the molecular requirements and interactions involved in RNA-triggered gene silencing in C. elegans. ? ? Determine the natural roles for RNA-triggered gene silencing and other homology-dependent gene silencing mechanisms during growth and development of C. elegans. ? ? Continue to develop genetic manipulation tools for C. elegans based on knowledge of gene lencing processes. ? ? We expect the results of our work to impact several diverse aspects of biomedical research. Studies of gene silencing have been of value from four perspectives. First, an understanding of gene silencing mechanisms allows us to better design systems for expressing specific genes in vivo. Such expression systems can provide significant advantages for applications such as gene therapy, analysis of mutant protein function, protein production, and general investigation of protein activity. Second, as we understand mechanisms of gene silencing, we acquire the ability to specifically and effectively silence genes within cells or in an organism, generating a significant toolkit for functional genomic research, and (perhaps in the long run) specific tools for gene-based therapeutics. Third, because gene-silencing mechanisms are indicative of a variety of cellular gene regulation mechanisms, work on gene silencing has provided valuable insights into normal gene regulation. Fourth, many gene silencing mechanisms reflect the response of the cell/organism to DNA or RNA that is viewed as foreign. This type of response forms the basis of mechanisms in place to resist """"""""selfish DNA"""""""" (or selfish RNA) in the form of viruses and transposons. Studies of gene silencing can thus extend our understanding of natural mechanisms used to fight viral infection (and by extension allow those mechanisms to be more readily induced or effected when needed).

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genetics Study Section (GEN)
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Greenberg, Judith H
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Carnegie Institution of Washington, D.C.
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Arribere, Joshua A; Fire, Andrew Z (2018) Nonsense mRNA suppression via nonstop decay. Elife 7:
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