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Peter Myler, Ph.D.

		Member, Seattle Biomedical Research Institute Research Professor, Department of Pathobiology, Department of Medical Education and Biomedical Informatics Adjunct Research Professor, Department of Global Health, University of Washington Email: peter.myler@sbri.org Diseases under study: African sleeping sickness, leishmaniasis, malaria

Mission
The Myler laboratory is devoted to the discovery of novel drug and vaccine strategies against global infectious disease. Our work focuses on using molecular, genomic and bioinformatic approaches to study gene expression in protozoan pathogens and using high-throughput techniques to elucidate the structure of bacterial and viral proteins.

Research
As part of an international collaboration with the Wellcome Trust Sanger Institute, The Institute for Genome Research and the Karolinska Institute, we have recently completed sequencing the genomes of three trypanosomatid parasites (Leishmania major, Trypanosoma cruzi and T. brucei). These projects (which are a joint effort with Ken Stuart) involved establishing a high-throughput sequencing capacity at SBRI, as well as a substantial bioinformatics capability. The bioinformatics group also played a key role in the Target Identification section of the Structural Genomics of Pathogenic Protozoa project (headed by Wim Hol at the University of Washington), by identifying genes from Leishmania, T. cruzi, T. brucei and Plasmodium falciparum which are suitable for high-throughput cloning, expression and crystallization in order to solve their three-dimensional structure.

The “Tritryp” genome sequences revealed unusual gene organization in trypanosomatids: the protein-coding genes are arranged in long polycistronic gene clusters, suggesting that these parasites employ unusual methods of transcription. Our laboratory seeks to characterize the components of the RNA polymerase (RNAP) II transcription complex and to elucidate the molecular mechanisms involved in RNAPII-mediated transcription of protein-coding genes in L. major. This research utilizes genome-scale approaches such as microarray-based transcript mapping and chromatin immunoprecipitation (ChIP-chip), as well as more traditional molecular approaches such as electrophoretic mobility shifts assays, affinity chromatography, and in vitro transcription.

In another project (in collaboration with Dan Zilberstein at the Technion Institute in Israel), we are using genome-wide approaches, such as mRNA expression microarrays and tandem mass spectrometry, to identify changes in gene expression during differentiation from the insect form (promastigotes) to the mammalian form (amastigotes) of L. donovani and to elucidate the signaling pathways involved in this process.

We have recently been award a large contact from NIAID to establish the Seattle Structural Genomics Center for Infectious Disease. The goal of this project, which involves collaboration with investigators at deCODE biostructures, the University of Washington and Battelle Memorial Institute, is to use state-of-the-art structural genomics technologies to create a collection of three dimensional protein structures from NIAID Category A-C pathogens and organisms causing emerging or re-emerging infectious diseases. The protein structures will be made available to the broad scientific community, where they will serve as a blueprint for structure-based drug development, as well as facilitating vaccine development and other basic research.

Themes
      *  regulation of gene expression in protozoan parasites
      *  genomics and bioinformatics
      *  structural genomics

Accomplishments
     *  Completed Tritryp genome sequences, providing the basis for discovery of new anti-trypanosomatid drugs
     *  Elucidated genome-wide transcription map of L. major and L. donovani
     *  Revealed hundreds of proteins that are up- or down-regulated during the transition between insect and mammalian stages of L. donovani

Support for Dr. Myler’s current research is provided by the National Institutes of Health (NIH) and the US-Israel Binational Science Foundation.

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