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Ulrich Muller
Biochemistry: catalytic RNA, orgin of life, therapeutic RNA splicing
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| Contact Information |
| Office: UH 5218 |
| Phone: (858) 534-6823 |
| Fax: (858) 822-4442 |
| Email: ufmuller@ucsd.edu |
| View group members
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| Education and Appointments |
| 2000 |
Ph.D., University of Technology Darmstadt, Germany
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| 1995 |
BS, LMU Munich, Germany
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| Awards and Academic Honors |
| 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 |
| Research Interests |
The Muller lab is interested in catalytic RNA molecules (ribozymes). We focus on two areas, ribozymes in the origin of life and ribozymes as therapeutic agents. In specific, we are developing ribozymes that feature improved substrate recognition and improved reaction pathways, compared with their current 'relatives'. This is accomplished using chemical modification of RNA, rational sequence design and in vitro evolution.
Ribozymes and the origin of life
Life probably originated via an evolutionary stage called the RNA world. In this scenario, RNAs served both as genomes and as catalysts, whose 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/protein life forms. Such a system would allow us to analyze its evolution on the molecular level because its small genome could be sequenced at every single generation.
We currently focus our efforts on the development of an efficient polymerase ribozyme. Such a ribozyme would be the central component of any self-replicating ribozyme system, being responsible for replicating RNA polymers. A polymerase ribozyme was developed in 2001 by the Bartel lab (Whitehead Institute), and several variants were generated in 2005 and 2007 by the Bartel lab and the Unrau lab (Simon Fraser University). These ribozymes are able to polymerize up to 20 nucleotides onto the 3'-terminus of an RNA primer, complementary to a template, with a fidelity above 97%. However, its efficiency is more than 10-fold below the level required for self-replication. We are equipping this ribozyme with new forms of substrate recognition, to make their polymerization efficiency sufficient for self-replication.
Ribozymes for therapeutic applications
Most ribozymes that were developed for therapeutic applications are aimed at the specific degradation of target mRNAs. We are using a different approach (pioneered by Bruce Sullenger, Duke University) that is aimed at repairing mutations in mRNAs. It uses group I introns to replace the mutated portion of the mRNA with a "healthy" sequence. This approach has several advantages, (1) it could be used for the treatment of loss-of-function mutations, (2) the repaired mRNA remains regulated by endogeneous mechanisms, and (3) occasional errors in this process are unlikely to have side effects. Currently, the main problem with these ribozymes is their low efficiency. We are improving the efficiency of these ribozymes, aiming for efficiencies that are sufficient for therapeutic applications.
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| Primary Research Area: |
Interdisciplinary Specialties: |
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Biochemistry
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Bioorganic
Macromolecular Structure
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| Image Gallery: |
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Figure 1: Lab members (from left to right): Karen, Uli, Janina |
Figure 2: Ribozymes and the Origin of Life |
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Figure 3: Uli Muller pipetting
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| Selected Publications |
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Köller J,
Müller UF,
Schmid B,
Missel A,
Kruft V,
Stuart K,
Göringer HU,
"Trypanosoma brucei gBP21. An arginine-rich mitochondrial protein that binds to guide RNA with high affinity." J Biol Chem 6(3749-57):
, 1997. [Go to PubMed]
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Lambert L,
Müller UF,
Souza AE,
Göringer HU,
"The involvement of gRNA-binding protein gBP21 in RNA editing-an in vitro and in vivo analysis." Nucleic Acids Res 6(1429-36):
, 1999. [Go to PubMed]
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Müller UF,
Lambert L,
Göringer HU,
"Annealing of RNA editing substrates facilitated by guide RNA-binding protein gBP21." EMBO J 6(1394-404):
, 2001. [Go to PubMed]
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Müller UF,
Göringer HU,
"Mechanism of the gBP21-mediated RNA/RNA annealing reaction: matchmaking and charge reduction." Nucleic Acids Res 2(447-55):
, 2002. [Go to PubMed]
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Müller UF,
Bartel DP,
"Substrate 2'-hydroxyl groups required for ribozyme-catalyzed polymerization." Chem Biol 9(799-806):
, 2003. [Go to PubMed]
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Brecht M,
Niemann M,
Schlüter E,
Müller UF,
Stuart K,
Göringer HU,
"TbMP42, a protein component of the RNA editing complex in African trypanosomes, has endo-exoribonuclease activity." Mol Cell 5(621-30):
, 2005. [Go to PubMed]
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Müller UF,
"Re-creating an RNA world." Cell Mol Life Sci 11(1278-93):
, 2006. [Go to PubMed]
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Müller UF,
Bartel DP,
"Improved polymerase ribozyme efficiency on hydrophobic assemblies." RNA 3(552-62):
, 2008. [Go to PubMed]
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Müller UF,
"Evolution of ribozymes in an RNA world." Chem Biol 8(797-8):
, 2009. [Go to PubMed]
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