个人简介

2013-2016 NASA research award 2012-2013 Hellman Fellow 2011-2012 Hellman Fellow 2008-2011 NSF research award 2004-2005 NRSA fellowship from the NIH 2001-2004 Postdoctoral award from the German Research Council (DFG) 2001-2003 Postdoctoral research, Whitehead Institute, Cambridge, MA

研究领域

Biochemistry

The Muller lab is interested in catalytic RNA molecules (ribozymes). We address two very different questions: (1) How did the RNA world, an early stage of life, function? To do this we develop catalytic RNAs by in vitro selection from random RNA sequences. Our long-term aim is to generate an RNA world organism and thereby recapitulate an early stage of life in the lab. (2) How can we change the sequence of disease-causing RNAs in cells? To do this we are re-engineering and evolving trans-splicing group I intron ribozymes in cells. Our long-term goal is to generate ribozymes that can be used in the therapy of diseases such as genetic disorders, viral infections, and cancer. Ribozymes and the origin of life The earliest evolutionary stages of life most likely included a stage called the RNA world. In this scenario, RNA served both as genome and as the only genome-encoded catalyst; these functions were later mostly overtaken by DNA and by proteins. We are trying to generate a self-replicating system of catalytic RNAs, mimicking an RNA world. If we were able to generate such a system, it could show us how an RNA world could function, and how an RNA world was able to evolve into today's DNA/RNA/protein life forms. The focus of our work is on ribozymes that generate chemically activated nucleotides, and polymerize chemically activated nucleotides. Both activities are essential for the self-replication of an RNA world organism. Our most recent work in this area identified ribozymes that are able to catalyze the triphosphorylation of RNA 5'-hydroxyl groups using trimetaphosphate, a compound that almost certainly existed on early Earth. These ribozymes were identified by in vitro selection from a pool with more than 10^14 different random sequences, and at least one of them shows a catalytic rate of 0.16 per minute under optimal conditions. These findings show that trimetaphosphate could have been used as energy source for RNA world organisms. Current efforts are to optimize and modify these ribozymes to integrate them into a larger system of self-replicating ribozymes, an RNA world organism. Ribozymes as tools for research and therapy Group I intron ribozymes are among the most well-studied and versatile ribozymes. In contrast to the natural, cis-splicing versions of group I intron ribozymes we are using engineered, trans-splicing group I introns. These ribozymes can specifically recognize target sites on mRNAs by base pairing and remove or replace sequences in the target mRNA. The trans-splicing group I intron ribozymes function in vitro and in cells, both in bacterial and in mammalian cells. However, two crucial steps need to be improved before these ribozymes could be used as tool in research and/or therapy: Ribozymes need to be delivered efficiently into cells, and the ribozymes need to work efficiently inside of cells. We are focusing on improving the efficiency of these ribozymes in cells. To do this we are using an evolutionary approach: Large libraries of ribozyme variants are generated by mutagenesis, then the most efficient of these ribozymes are selected and amplified. After multiple cycles of this evolution process we identified ribozymes with mutations that strongly increase ribozyme efficiency in cells. We anticipate that future evolution and optimization will make these ribozymes useful as tools in research and therapy.

近期论文

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Amini ZN, Olson KE, Müller UF, "Spliceozymes: Ribozymes that Remove Introns from Pre-mRNAs in Trans.", PLoS One, 2014, Vol. 9, Issue 7, e101932 [View Abstract] Moretti JE, Müller UF, "A ribozyme that triphosphorylates RNA 5'-hydroxyl groups.", Nucleic Acids Res, 2014, [View Abstract] Müller UF, Tor Y, "Citric acid and the RNA world.", Angew Chem Int Ed Engl, 2014, Vol. 53, Issue 21, 5245-7 [View Abstract] Olson KE, Dolan GF, Müller UF, "In vivo evolution of a catalytic RNA couples trans-splicing to translation.", PLoS One, 2014, Vol. 9, Issue 1, e86473 [View Abstract] Amini ZN, Müller UF, "Low selection pressure aids the evolution of cooperative ribozyme mutations in cells.", J Biol Chem, 2013, Vol. 288, Issue 46, 33096-106 [View Abstract] Dolan GF, Müller UF, "Trans-splicing with the group I intron ribozyme from Azoarcus.", RNA, 2013, [View Abstract] Meluzzi D, Olson KE, Dolan GF, Arya G, Müller UF, "Computational prediction of efficient splice sites for trans-splicing ribozymes.", RNA, 2012, Vol. 18, Issue 3, 590-602 [View Abstract] Olson KE, Müller UF, "An in vivo selection method to optimize trans-splicing ribozymes.", RNA, 2012, Vol. 18, Issue 3, 581-9 [View Abstract] Yao C, Moretti JE, Struss PE, Spall JA, Müller UF, "Arginine cofactors on the polymerase ribozyme.", PLoS One, 2011, Vol. 6, Issue 9, e25030 [View Abstract] Yao C, Müller UF, "Polymerase ribozyme efficiency increased by G/T-rich DNA oligonucleotides.", RNA, 2011, Vol. 17, Issue 7, 1274-81 [View Abstract] Müller UF, "Evolution of ribozymes in an RNA world.", Chem Biol, 2009, Vol. 16, Issue 8, 797-8 [View Abstract] Müller UF, Bartel DP, "Improved polymerase ribozyme efficiency on hydrophobic assemblies.", RNA, 2008, Vol. 14, Issue 3, 552-62 [View Abstract] Müller UF, "Re-creating an RNA world.", Cell Mol Life Sci, 2006, Vol. 63, Issue 11, 1278-93 [View Abstract] Müller UF, Bartel DP, "Substrate 2'-hydroxyl groups required for ribozyme-catalyzed polymerization.", Chem Biol, 2003, Vol. 10, Issue 9, 799-806 [View Abstract] Müller UF, Göringer HU, "Mechanism of the gBP21-mediated RNA/RNA annealing reaction: matchmaking and charge reduction.", Nucleic Acids Res, 2002, Vol. 30, Issue 2, 447-55 [View Abstract] Müller UF, Lambert L, Göringer HU, "Annealing of RNA editing substrates facilitated by guide RNA-binding protein gBP21.", EMBO J, 2001, Vol. 20, Issue 6, 1394-404 [View Abstract]