Description:
Princeton Docket # 16-3188-1
Researchers at Princeton University, Department of Molecular Biology, have developed a novel research and diagnostics tool for detection of an intracellular stress signal 2',5'-linked oligoadenylate (2-5A).
2-5A is a small RNA-like signal that activates the human receptor pseudokinase, RNase L. RNase L is a candidate tumor suppressor in hereditary prostate cancer and breast cancer. RNase L is key for antibacterial defense, antiviral defense, growth, insulin response and adipocyte differentiation. Researchers found that the RNase L•2-5A complex inhibits cell proliferation and adhesion by activating the same RNA decay program as the metastasis-controlling microRNA, miR-200. RNase L achieves this directly, without using miR-200.
Researchers solved the crystal structure of the 2-5A-sensor domain of human RNase L, which provided the rationale for building light-emitting reporter proteins for monitoring 2-5A biochemically, in live cells and in animals. This platform can be used for studies of the RNase L pathway, probing the 2-5A production in disease models or patient samples, and is scalable for high-throughput screening for small molecule modulators of the 2-5A/RNase L signaling in live cells and in biochemical assays.
Elevated 2-5A levels predict an active miR-200-like program, and could mark a low-proliferative cellular state, apoptosis, a presence of a viral infection, cell damage, interferon response, inflammation, cell loss, or a degenerative disease. Low 2-5A levels are expected to mark a highly proliferative state and metastasis. Small molecule modulators discovered with the reporter system are thus expected to provide corrective measures for infectious, inflammatory or neoplastic diseases.
Applications
• High-throughput screening platform for new types of drugs
o anti-proliferative
o anti-metastatic
o anti-viral
• Diagnostics/biomarker discovery for
o infections
o cancer & EMT
o inflammatory diseases
• Research tool for
o interferon/inflammatory response
o cancer
Advantages
• Light-based signal
• First sensor capable of detecting 2-5A in live cells
• Suitable for 2-5A detection in tissue samples
• Scalable for high-throughput drug screens
• Compatible with biochemical assays and live cell assays
Publications
Han, Y., Whitney, G., Donovan, J., and Korennykh, A. Innate Immune Messenger 2-5A Tethers Human RNase L into Active High-Order Complexes. Cell Reports 2(4), (2012), pp. 902-913.
Jesse Donovan, Matt Dufner, Alexei Korennykh. Structural basis for cytosolic double-stranded RNA surveillance by human oligoadenylate synthetase 1.
PNAS 110(5), (2013) pp. 1652-1657
Sneha Rath, Jesse Donovan, Gena Whitney, Alisha Chitrakar, Wei Wang, and Alexei Korennykh, Human RNase L Tunes Gene Expression by Selectively Destabilizing the MicroRNA-Regulated Transcriptome. PNAS 112(52), (2015) pp. 15916–15921
The Faculty Inventor
Alexei Korennykh is an Assistant Professor of Molecular Biology. The central theme of his research is to understand mechanisms of RNA-dependent signal transduction in the human immune system and during stress responses associated with human diseases. They use X-ray crystallography, biochemistry, biophysics and cell biology to understand structures, functions and regulation of the key human proteins, RNA, intracellular messengers, and their complexes.
Intellectual Property & Development status
Patent protection is pending.
Princeton is currently seeking commercial partners for the further development and commercialization of this opportunity.
Contact:
Laurie Tzodikov
Princeton University Office of Technology Licensing • (609) 258-7256• tzodikov@princeton.edu
Xin (Shane) Peng
Princeton University Office of Technology Licensing • (609) 258-5579• xinp@princeton.edu