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grant:DDVU02/5/2010, Design and applications of RNA biosensors in vitro and in vivo awarded by the Bulgarian National Science Fund (BNSF)

Project objectives:

The main goal of this project is to continue a very successful research in the field of RNA synthetic and computational biology, and nanobiotechnology started by the project leader Dr. rer. nat. Robert Penchovsky several years ago as a postdoctoral fellow at Yale University. Results of this research have been published in high impact factor journals such as Nature Biotechnology and have over 100 citations. This research is described in two News and Views papers published in Nature Biotechnology and Nature Methods as a “ground breaking”3,4. Moreover, the management of Yale University has well realized the huge practical importance of this research and has filed a world-wide patent application as the project leader is one of the two co-authors of the patent. Therefore, the current project proposal gives a unique opportunity for the Bulgarian science to catch up with leading world research centers such as Yale University in the strategically important fields of RNA synthetic biology and nanobiotechnology. The implementation of the project will be opening novel scientific areas in synthetic biology in Bulgaria and worldwide both in terms of research and teaching. Furthermore, any aspect of the proposed research has a practical application that may be a subject of future commercialization within the nanobiotechnology and pharmaceutical industry not only in Bulgaria but also in Germany and the USA. This project will facilitate the transfer of know-how from Yale University to Sofia University in the field of RNA synthetic biology that is a rare opportunity and must be highly appreciated. The main scientific hurdles in front of the proposed research have been already solved by the research done at Yale University. This gives a high confidence in the feasibility of the project objectives set in the current project. The main goals of the project are to utilize computationally designed allosteric ribozymes as biosensors that can work both in vitro and in vivo. It is important to note that the proposed project is not risky at all since is based on already proven technology. The risk of the initial stages of technology development has been already taken by Yale University and USA research funding bodies such as DARPA, NSF, and NIH. Therefore, the Bulgarian NSF has the rare opportunity to fund such a developed project at stage when the technology is working and the benefits are clear without taking any risk for initial technology development. We do hope that the Bulgarian NSF will have the wisdom to appreciate this chance and fully support the proposed project. The proposed project is logically divided into two stages. The first stage of the project concerns computational design and biochemical tests of several types of allosteric ribozymes. The ribozymes are designed by a highly efficient algorithm to sense the presence of small molecules or short RNA and DNA molecules. The ribozymes can be designed to work as biosensors that have various Boolean logic functions including YES, NOT, AND, and OR. In the second stage of the project designer ribozymes will be employed as biosensors in many practical applications in vitro and in vivo. In vitro applications include set up of molecular computing devices and reporter systems in high-throughput screening of chemical libraries for antibacterial drug discovery. In vivo applications include employing designer ribozymes as synthetic riboswitches for exogenous control of gene expression in E. coli, Yeast, and human cell lines with many practical applications including gene therapy of many forms of cancer. The project has two collaborates from Germany, who will contribute to its successful implementation. Apart from the proposed novel and cutting edge research, teaching of students is a very important part of the project. There are six students from Sofia University, who are part of the research team of the project. The students are carefully selected based on their motivation to learn novel methods and techniques. The students are from different grates to ensure continues training throughout the full three years of the project. They will have an opportunity to collaborate with researchers from Germany, Austria, the USA in the field of RNA synthetic biology and nanobiotechnology that will be very beneficial for their early career development.

This grant was very successfully completed and evaluated with the highest score. The results were published in 9 research papers with a common impact factor of 34, 7 master students graduated, and 3 talks on 3 conferences for only 42 400 EUR in July 2014 as detailed below.

Publications:

1. Penchovsky, R. Computational design of allosteric ribozymes as Molecular Biosensors, Biotechnology Advances, 32, 1015-1027 (2014). – (IF:11.88, Q1, Scopus).

2. Penchovsky, R. Chapter 16: Nucleic Acids-based Nanotechnology; Engineering Principals and Applications, Handbook of Research on Nanoscience, Nanotechnology, and Advanced Materials; Engineering Sciences Reference: An Imprint of IGI Global DOI: 10.4018/978-1-4666-5824-0.ch016, 414-430 (2014).

3. Penchovsky, R & Kostova, G. Computational selection and experimental validation of allosteric ribozymes that sense a specific sequence of human telomerase reverse transcriptase mRNAs as universal anticancer therapy agents. Nucleic Acid Therapeutics, 23, 408-431 (2013). - (IF:2.91, Q1, Scopus).

4. Penchovsky, R. Present and Future RNA-based Approaches to Medical Genomics, International Journal of Genomic Medicine, 10.4172/2332-0672.1000110, 1(2), 1-7 (2013).

5. Penchovsky, R. Programmable and automated bead-based microfluidics for versatile DNA microarrays under isothermal conditions. Lab on a chip;13, 2370-80 (2013) - (IF:6.41, Q1, Scopus).

6. Penchovsky, R. Computational design and biosensor applications of small molecule-sensing allosteric ribozymes. ACS Biomacromolecules, 14, 1240–1249 (2013). – (IF:5.77, Q1, Scopus).

7. Penchovsky, R. & Stoilova C.C. Riboswitch-based antibacterial drug discovery using high-throughput screening methods. Expert Opinion on Drug Discovery, 8, 65-82. (2013).- (IF:3.5, Q1, Scopus).

8. Penchovsky, R. Engineering integrated digital circuits with allosteric ribozymes for scaling up molecular computation and diagnostics. ACS Synthetic Biology, 1, 471-482 (2012). – (IF: 3.95, Q1, Scopus).

9. Penchovsky, R. Chapter 5: Engineering Gene Control Circuits with Allosteric Ribozymes in Human Cells as a Medicine of the Future, in the book “Quality Assurance in Healthcare Service Delivery, Nursing and Personalized Medicine: Technologies and Processes”, Publisher IGI Global, DOI: 10.4018/978-1-120-7, 71-96 (2012).

Date: 1 December 2010 - 1 June 2014

Conferences:

1. Bioscience - new opportunities, Sofia, Bulgaria

2. Jubilee Conference 125 years of Mathematics and Natural Sciences,Sofia, Bulgaria

3. National Conference of Biotechnology at the Faculty of Biology, Sofia, Bulgaria

Graduated Master Students:

7 master students are graduated working on the project (see the table from number 1 to 7)