microRNA (miRNA) are a recently uncovered class of regulatory RNAs which help to regulate gene expression, and control cell function. Over 2,000 human miRNAs have been discovered. Many miRNAs have tumor suppressor or oncogenic functions, and miRNA dysregulation has been shown to play a key role oncogenesis, metastasis, and even chemoresistance. Although much has been learned about miRNA biology, as the number of new miRNA genes have been discovered it has become increasingly challenging to annotate relevant miRNA regulatory networks. A critical limitation has been the lack of high-throughput, biological approaches for genome-wide analysis of miRNA behavior. In this R33 proposal, we will develop and validate a new technology and methodology that can be used to: (1) Measure the activity of each and every miRNA within a cell, at single cell resolution, and (2) Identify optimal synthetic miRNA binding sites that can be used to improve the targeting of suicide vectors and oncolytic viruses being developed for cancer therapies. Our technology will have major utility for expanding our understanding of cancer biology, for generating tools to study and even track specific cancer cell subsets, such as cancer stem cells, for screening for miRNA modulating drugs, and for developing novel therapies that better target tumor cells for destruction.
In this proposal, we will expand the development and validation of a new technology and methodology that can be used to: (i) measure the activity of each and every miRNA within a cell, and (ii) generate therapeutic vectors with cell type specificity. Our technology has major applications for expanding our understanding of cancer biology, for generating tools to study and track specific cancer cell subsets, for screening for miRNA modulating drugs, and for developing novel therapies that better target tumor cells for destruction.
| Wroblewska, Aleksandra; Dhainaut, Maxime; Ben-Zvi, Benjamin et al. (2018) Protein Barcodes Enable High-Dimensional Single-Cell CRISPR Screens. Cell 175:1141-1155.e16 |
| Strub, Thomas; Ghiraldini, Flavia G; Carcamo, Saul et al. (2018) SIRT6 haploinsufficiency induces BRAFV600E melanoma cell resistance to MAPK inhibitors via IGF signalling. Nat Commun 9:3440 |
| Kidd, Brian A; Wroblewska, Aleksandra; Boland, Mary R et al. (2016) Mapping the effects of drugs on the immune system. Nat Biotechnol 34:47-54 |
| Jayaprakash, Anitha D; Benson, Erica K; Gone, Swapna et al. (2015) Stable heteroplasmy at the single-cell level is facilitated by intercellular exchange of mtDNA. Nucleic Acids Res 43:2177-87 |
| Israelow, Benjamin; Mullokandov, Gavriel; Agudo, Judith et al. (2014) Hepatitis C virus genetics affects miR-122 requirements and response to miR-122 inhibitors. Nat Commun 5:5408 |
