个人简介

Ph.D. 2001, Duke University

研究领域

Understanding the mechanisms of protein expression/folding and degradation

Our laboratory has a general interest in understanding the mechanisms of protein expression, folding and degradation. We investigate how cells maintain a homeostatic balance between these processes, and how this homeostasis is effected by disease and aging. The projects in the lab draw on a number of disciplines including cell biology, biochemistry, systems biology and computational biology. Two current projects are described below: The mechanism of prion propagation and pathogenesis Most proteins populate a single, ordered three-dimensional structure in solution. However, a subset of proteins, termed prions, have the capacity to fold into alternative self-replicating conformations, enabling a single polypeptide sequence to be associated with multiple phenotypes. The ability of prions to fold into diverse meta-stable, self-seeding conformations facilitates two protein-based functionalities that were previously thought to require the involvement of nucleic acid-based genetic elements: infectivity and heritability. Although historically associated with a group of neurodegenerative disorders in mammals, prions have now been discovered in a number of organisms and have been implicated in the regulation of non-pathogenic biological activities including translation, transcription, mating compatibility and memory. Current projects in the lab are seeking to understand the cellular mechanisms of prion propagation and pathogenesis - and to identify effective therapeutics against prion diseases. Global analysis of protein expression and turnover A central focus of the lab is the development of novel methodologies for system-wide analysis of protein homeostasis. Specifically, we are developing proteomic techniques that can measure the kinetics of protein formation and degradation on proteome-wide scales. We are using these approaches to assess the impact of protein aggregate accumulation on proteome dynamics in models of aging and neurodegenerative diseases. It is hoped that these proteomic screens will identify novel molecular pathways involved in age-dependant neurodegenerative diseases.

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Guan, S., Price, J.C., Prusiner, S.B., Ghaemmaghami, S., Burlingame, A.L. "A data processing pipeline for mammalian proteome dynamics studies using stable isotope metabolic labeling," Mol Cell Proteomics 2011, PubMed PMID: 21937731. Poncet-Montange, G., St. Martin, S.J., Bogatova, O.V., Prusiner, S.B., Shoichet, B.K., Ghaemmaghami, S. "A survey of antiprion compounds reveals the prevalence of non-PrP molecular targets," J Biol Chem. 2011, 5;286(31), 27718-28. Ghaemmaghami, S., Watts, J.C., Nguyen, H.O., Hayashi, S., Dearmond, S.J., Prusiner, S.B. "Conformational Transformation and Selection of Synthetic Prion Strains," J Mol Biol. 2011, PubMed PMID: 21839745. Price, J.C., Guan, S., Burlingame, A., Prusiner, S.B., Ghaemmaghami, S. "nalysis of proteome dynamics in the mouse brain," Proc Natl Acad Sci U S A 2010, 107(32), 14508-13. Ghaemmaghami, S., Ullman, J., Ahn, M., St. Martin, S., Prusiner, S.B. "Chemical induction of misfolded prion protein conformers in cell culture," J Biol Chem. 2010, 285(14), 10415-23. Epub 2009 Dec 2. PubMed PMID: 19955177; PubMed Central PMCID: PMC2856248.