User:Catherine Gorick/Notebook/Exosomal miRNA drug delivery system
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Katie Gorick and Amelia Mockett 20.109 Spring 2013 W/F Section Orange Team
Small, noncoding RNA genes known as microRNAs have been shown to be transported out of cells by cell-derived vesicles called exosomes. The exosomes latch on to target cells and release their contents, including the microRNAs, into these target cells. This is now believed to be a mechanism of cell-cell signalling and communication. We propose to create a therapeutic RNA-binding protein associated with one of these preferentially exported microRNA genes, so that the drug is transferred out of the sender cell along with the microRNA. It will then be delivered to a target cell, where the therapeutic protein can act to fight off infection or inhibit disease.
Relevant Studies and Background Information
Rabinowits, G., Gercel-Taylor, C., Day, J., Taylor, D., & Kloecker, G. (2009). Exosomal microRNA: A diagnostic marker for lung cancer. Clinical Lung Cancer, 10(1): 42-46.
This article described a study investigating microRNAs (miRNAs), which are small noncoding RNA genes. These miRNAs were found to be expressed abnormally in certain cancers. The miRNAs have been detected in exosomes, and there was a significant difference in exosome and miRNA levels between cancer patients and healthy individuals, suggesting that circulating exosomal miRNA could be used as a screen for certain cancers.
Stoorvogel, W. (2012). Functional transfer of microRNA by exosomes. Blood, 119(3): 646-648.
This article suggests that cells can communicate and signal one another through exosomal microRNAs. The exosomes are preferentially loaded with specific miRNAs, and then leave the cell to fuse with a different target cell. There, they release their enclosed miRNAs, which play some role in the target cell. In particular, the article describes the ability of the transferred miRNAs to silence mRNA in the cytosol of the target cell.
Wilda, M., Fuchs, U., Wossmann, W., & Borkhardt, A. (2002). Killing of leukemic cells with a BCR/ABL fusion gene by RNA interference (RNAi). Oncogene, 21(37): 5716-5724.
This study examined the phenomenon of RNA interference (RNAi). This phenomenon uses small double-stranded RNA (dsRNA) segments to silence the expression of the homologous gene mRNA. The authors of this paper created dsRNA to target the M-BCR/ABL (oncogene) fusion site to kill leukemic cells via rearrangement. The result was decreased BCR/ABL mRNA and oncoprotein, as well as increased apoptotic cell death.
Flach, J., Bossie, M., Vogel, J., Corbett, A., Jinks, T., Willins, D., & Silver, P. (1994). A yeast RNA-binding protein shuttles between the nucleus and the cytoplasm. Moleclar Cell Biology, 14(12): 8399-8407.
This study analyzed the movement of RNA-binding proteins within the cell. It was discovered that a yeast gene called NPL3 codes for proteins with RNA-binding motifs. These proteins can move in association with their bound RNA as it leaves the nucleus of the cell, so the proteins are able to be shuttled in and out of the nucleus.