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[原创]PostDoc position available-SiRNA and RN

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golem 发表于 2006-3-30 22:46:00 | 显示全部楼层 |阅读模式
University of Wisconsin

Please contact the P.I at sgkennedy@wisc.edu

http://www.wisc.edu/molpharm/faculty/kennedy.html

Small RNAs and RNAi



Small RNAs of 21–24 nucleotides in length function in a remarkably wide range of biological processes, including gene silencing, translational regulation, heterochromatin formation, developmental timing, antiviral defense, and genome rearrangement. The long-term interest of my laboratory is to gain a molecular understanding of the endogenous biological functions of small RNAs. In particular, we are interested in the evolutionarily conserved process of RNA interference (RNAi). Exposure of many organisms to double-stranded (ds) RNA causes the degradation of mRNA molecules containing sequences homologous to the trigger dsRNA. dsRNAs are processed by the RNase III enzyme Dicer (DCR-1) into small RNAs [termed small interfering RNAs (siRNAs)] which hybridize to and induce the degradation of cognate mRNAs. This gene-silencing phenomenon has been termed RNA interference (RNAi).

We are undertaking genetic screens in the model organism C. elegans to identify and characterize the RNAi machinery. These screens are targeting genes that are required for appropriate organismal responses to dsRNA and genes which function to negatively regulate RNAi. An additional goal of the laboratory is to further our understanding of the endogenous biological functions of this conserved RNAi machinery. Several possibilities for these functions include: protecting organisms from parasitic nucleic acids such as viruses and transposons, the regulation of transcription and chromatin structure, and the post-transcriptional regulation of cellular mRNAs. We are using genetics, molecular biology, and biochemistry to answer these questions.

Much of the RNAi machinery is conserved in mammals, indicating that research on RNAi in model organisms such as C. elegans will not only be fundamental to our understanding of the biology of RNAi, but also instrumental in the rational use of RNAi technology in mammalian systems, and in the use of RNAi as a possible therapeutic to treat human disease.


Identification and Characterization of the RNAi machinery:

We have undertaken a genetic screen targeting regulators of RNAi. To date this screen has identified five genes: ERI-1 through ERI-5. We have shown that ERI-1 encodes for an evolutionarily conserved enzyme that we hypothesize functions to regulate RNAi by inactivating the siRNAs produced by the RNase III enzyme DICER. In addition, we have shown that ERI-1 through ERI-5 function in a large protein complex that physically associates with the catalytic engine of RNAi, DICER. Finally, we have shown that the ERI/DICER complex targets a subset of cellular mRNAs for degradation by an RNAi-like mechanism. We have termed this novel mode of gene regulation endogenous RNAi.




Projects in the laboratory will include 1) Molecular characterization of the ERI/DICER complex 2) Determination of the endogenous biological function(s) of ERI-1 and the ERI/DICER complex. 3) Determination of the scale and mechanism of endogenous RNAi 4) Testing for functional conservation of the ERI/DICER complex in mammals.

Genomic Analysis of RNAi:

We have also undertaken a genome-wide RNAi screen designed to comprehensively identify all non-essential factors required for RNAi in C. elegans. This genomic screen has identified 92 additional putative RNAi genes. Projects in the lab will include 1) Placing these novel factors into genetic and molecular pathways using classic genetic analysis, phenotypic analysis, expression profiling, and proteomic analysis 2) Determination of the molecular roles of these factors in RNAi and analysis of the endogenous function of these genes in the biology of C. elegans 3) Additional Genome-wide RNAi screens targeting essential RNAi genes.



Selected Publications:
  • Wang D., Kennedy S., Conte D., Kim J., Gabel H., Kamath R., Mello C., Ruvkun G., "Somatic misexpression of germline P granules and enhanced RNA interference in C. elegans retinoblastoma pathway mutants" Nature. In Press.

  • Sieburth D., Ch'ng Q., Dybbs M., Tavazoie M., Kennedy S., Wang D., Dupuy D., RualR., Hill D., Vidal M., Ruvkun G., Kaplan J. "Systematic Analysis of Synaptic Protein Function and Localization" Nature. In press.

  • Kim, J. K.; Gabel, H. W.; Kamath, R. S.; Tewari, M.; Pasquinelli, A.; Rual, J. F.; Kennedy, S.; Dybbs, M.; Bertin, N.; Kaplan, J. M.; Vidal, M.; Ruvkun, G., Functional Genomic Analysis of RNA Interference in C. elegans. Science, 2005.

  • Kennedy, S., Wang D., Ruvkun G., A conserved siRNA-degrading RNase negatively regulates RNA interference in C. elegans. Nature 427, 645-9 (2004).

  • Lee, S. S., Kennedy, S., Tolonen, A. C. & Ruvkun, G. DAF-16 target genes that control C. elegans life-span and metabolism. Science 300, 644-7 (2003).

  • Kennedy SG, Kandel ES, Cross TK, Hay N. Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol and Cell Biology. 19(8):5800-10 (1999).

  • Gingras, AC*, Kennedy SG*, O'Leary, MA, Sonenberg, N., Hay, N. 4E-BP1, a Repressor of mRNA Translation, is Phosphorylated and Inactivated by the Akt(PKB) Signaling Pathway. Genes Dev, 12:502-513 (1998).

  • Kennedy SG., Wagner AJ., Conzen SD., Jordan J., Bellacosa A., Tsichlis PN., Hay N. The PI 3-Kinase/Akt Signaling Pathway Delivers an Anti-Apoptotic Signal. Genes Dev, 11:701-713. (1997).
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