个人简介

Dorothea grew up in the most beautiful city in Germany: Hamburg. She went to college at the University of Wuerzburg and did her Diploma work at UC Berkeley. She decided she liked the United States for many reasons that include Thanksgiving (and also German beers are overrated), so she stayed at Berkeley for her Ph.D. She worked in the Raymond and Bergman labs, studying host-guest systems and their application to catalysis. She then moved across the Bay to UCSF, where she joined the Shokat lab to investigate signal transduction pathways. She is now attempting to be a chemical biologist at Princeton and is hoping to elucidate the specific signaling functions of a number of fascinating cellular metabolic messengers.

研究领域

Elucidating cellular signaling functions of small molecule second messengers.

Cells are able to process an enormous amount of information about their environment and their internal status via highly regulated signaling pathways. Small molecule second messengers (for example cAMP, Ca2+, and nitric oxide) are an important component of signal transduction cascades. These second messengers are diffusible signaling molecules, which can be rapidly generated or released to then regulate the activity of particular effector proteins. Our lab focuses on two classes of metabolic second messengers, namely the diphosphoinositol polyphosphates (PP-IPs) and inorganic polyphosphates (polyP), because these molecules harness a recurring theme in signaling: phosphate groups. A recently discovered group of eukaryotic second messengers are the highly phosphorylated inositides. Among the many derivatives of the inositol phosphate messengers is a subgroup that possesses high energy diphosphate groups. This intriguing class of diphosphoinositol polyphosphates (PP-IPs) has been linked to several cellular functions such as telomere maintenance, vesicular trafficking, and protein phosphorylation. Moreover, it has been demonstrated that the PP-IPs are intimately involved in insulin secretion, glucose uptake, and the metabolic state of cancer cells. Inorganic polyphosphate (polyP) is a linear polymer in which tens to hundreds of phosphate residues are linked by phosphoanhydride bonds. The biological functions of polyP have mainly been investigated in microorganisms, although evidence is accumulating that polyP carries many important functions in mammalian systems. These functions include blood coagulation, osteoblast calcification, and breast cancer cell proliferation. To date many of the signaling functions of PP-IPs and polyP have remained elusive, because these metabolites are difficult to study with standard cell biology techniques. Their chemical tractability, however, provides the unique opportunity to investigate their functions with chemical tools. With these probes we hope to be able to answer the following questions: Which proteins interact physically with PP-IPs? Which proteins are phosphorylated by PP-IPs? What are the metal-binding properties of PP-IPs? How are PP-IPs linked to cellular energy homeostasis? Which proteins are involved in polyP biosynthesis? Which proteins interact physically with polyP? How does polyP interact with specific metal cations? Can we use polyP for the bioremediation of toxic metals? Investigating these problems requires an interdisciplinary approach that combines synthetic organic and inorganic chemistry with biochemical analyses and molecular and cellular biology techniques. Initial efforts will focus on understanding the molecular signaling mechanisms by employing chemical reagents. These reagents are then to be evaluated in the relevant cell models, in combination with different genetic perturbations. This will allow us to place the second messengers into their cellular context. Ultimately, this research will highlight new drug targets and can thus be exploited for the design of novel therapeutics.

近期论文

查看导师新发文章 （温馨提示：请注意重名现象，建议点开原文通过作者单位确认）

John H. Conway and Dorothea Fiedler. "An Affinity Reagent for the Recognition of Pyrophosphorylated Peptides" Angew. Chem. Int. Ed. 2015, 54, Early View. Lisa M. Yates and Dorothea Fiedler. "Establishing the Stability and Reversibility of Protein Pyrophosphorylation with Synthetic Peptides" ChemBioChem 2015, 16, 415-423. Highlighted in ChemViews Magazine: Lost in Post-Translation. Lisa M. Yates, Alan M. Marmelstein, and Dorothea Fiedler. "Synthetic Pyrophosphorylation Methods and Their Use in Chemical Biology." Synlett 2014, 25, 2239-2245. Mingxuan Wu, Lucy S. Chong, Samanta Capolicchio, Henning J. Jessen, Adam C. Resnick, and Dorothea Fiedler. "Elucidating Diphosphoinositol Polyphosphate Function with Nonhydrolyzable Analogues" Angew. Chem. Int. Ed. 2014, 53, 7192-7197. Feng Rao, Jiyoung Cha, Jing Xu, Risheng Xu, M. Scott Vandiver, Richa Tyagi, Robert Tokhunts, Michael A. Koldobskiy, Chenglai Fu, Roxanne Barrow, Mingxuan Wu, Dorothea Fiedler, James C. Barrow, Solomon H. Snyder. " Inositol Pyrophosphates Mediate the DNA-PK/ATM-p53 Cell Death Pathway by Regulating CK2 Phosphorylation of Tti1/Tel2." Mol. Cell 2014, 54, 119-132. Alan M. Marmelstein, Lisa M. Yates, John H. Conway, and Dorothea Fiedler. "Chemical Pyrophosphorylation of Functionally Diverse Peptides." J. Am. Chem. Soc. 2014, 136, 108-111. Highlighted in JACS Spotlights: J. Am. Chem. Soc. 2014, 136, 821 Mingxuan Wu, Barbara E. Dul, Alexandra J. Trevisan, and Dorothea Fiedler. "Synthesis and characterization of non-hydrolysable diphosphoinositol polyphosphate messengers." Chem. Sci. 2013,4, 405-410. J. I. Kliegman, D. Fiedler, C. J. Ryan, Y. F. Xu, X. Y. Su, D. Thomas, M. C. Caccese, A. Cheng, M. Shales, J. D. Rabinowitz, N. J. Krogan, K. M. Shokat. " Chemical Genetics of Rapamycin-Insensitive TORC2 in S. cerevisiae." Cell Reports 2013, 5, 1725–1736. J. L. Nakamura, C. Phong, E. Pinarbasi, S. C. Kogan, S. Vandenberg, A. E. Horvai, B. A. Faddegon, D. Fiedler, K. M. Shokat, B. T. Houseman, R. Chao, R. O. Pieper, K. Shannon. “Dose-dependent effects of focal fractionated irradiation on secondary malignant neoplasms in Nf1 mutant mice.” Cancer Res. 2011, 71, 106-15. S. van Wageningen, P. Kemmeren, P. Lijnzaad, T. Margaritis, J. J. Benschop, I. J. de Castro, D. van Leenen, M. J. A. Groot Koerkamp, C. W. Ko, A. J. Miles, N. Brabers, M. O. Brok, T. L. Lenstra, D. Fiedler, L. Fokkens, R. Aldecoa, E. Apweiler, V. Taliadouros, K. Sameith, L. A. L. van de Pasch, S. R. van Hooff, L. V. Bakker, N. J. Krogan, B. Snel, F. C. P. Holstege. “Functional overlap and regulatory links shape genetic interactions between signaling pathways.” Cell 2010, 143, 991-1004. Highlighted in Cell 2010, 143, 867-869. S. Bandyopadhyay, M. Mehta, D. Kuo, M. K. Sung, R. Chuang, E. J. Jaehnig, B> Bodenmiller, K. Licon, W. Copeland, M. Shales, D. Fiedler, J. Dutkowski, A. Guénolé, H. van Attikum, K. M. Shokat, R. D. Kolodner, W. K. Huh, R. Aebersold, M. C. Keogh, N. J. Krogan, T. Ideker. “Rewiring of genetic networks in response to DNA damage.” Science 2010, 330, 1385-1389. P. Beltrao, J. C. Trinidad, D. Fiedler, A. Roguev, W. A. Lim, K. M. Shokat, A. L. Burlingame, N. J. Krogan. “Evolution of phosphoregulation: comparison of phosphorylation patterns across yeast species.” PLoS Biol. 2009, 7, e1000134. D. Fiedler , H. Braberg, M. Mehta, G. Chechik, G. Cagney, P. Mukherjee, A. C. Silva, M. Shales, S. R. Collins S. van Wageningen, P. Kemmeren, F. C. P. Holstege, J. S. Weissman, M. Christopher-Keogh, D. Koller, K. M. Shokat, N. J. Krogan. “Functional organization of the S. cerevisiae phosphorylation network.” Cell 2009, 136, 952- 963. Cover Picture T. Okuzumi, D. Fiedler, C. Zhang, D. C. Gray, B. Aizenstein, R. Hoffman, K. M. Shokat. “Inhibitor hijacking of Akt activation.” Nat. Chem. Bio. 2009, 5, 484-493. H. Wang, B. Kakaradov, S. R. Collins, L. Karotki, D. Fiedler, M. Shales, K. M. Shokat, T. Walther, N. J. Krogan, D. Koller. “A complex-based reconstruction of the S. cerevisiae interactome.“ Mol. Cell. Proteomics 2009, 8, 1361-1381. L. M. Sly; M. J. Hamilton; E. Kuroda; V. W. Ho; F. L. Antignano; S. L. Omeis; C. J. van Netten-Thomas; D. Wong; H. K. Brugger; O. Williams; M. E. Feldman; B. T. Houseman; D. Fiedler; K. M. Shokat; G. Krystal. “ SHIP prevents lipopolysaccharide from triggering an antiviral response in mice.” Blood 2009, 113, 2945-2954. J. Wang, Z. Knight, D. Fiedler, O. R. Williams, K. M. Shokat, D. Pearce. “Activity of the p110-alpha subunit of phosphatidylinositol-3-kinase is required for activation of epithelial sodium transport.” Am. J. Physiol. 2008, 295, F843-F850. T. Tamguney, C. Zhang, D. Fiedler, K. M. Shokat, D. Stokoe. “Analysis of 3-phosphoinositide-dependent kinase-1 signaling and function in ES Cells.” Exp. Cell Res. 2008, 314, 2299-2312. J. S. Mugridge, D. Fiedler, K. N. Raymond. “A Ferrocene-Based Catecholamide Ligand: the Consequences of Ligand Swivel for Directed Supramolecular Self-Assembly.” J. Coord. Chem. 2010, 63, 2779 – 2789. M. Pluth, D. Fiedler, R. G. Bergman, K. N. Raymond. “Molecular recognition and self-assembly special feature: Encapsulation and characterization of proton-bound amine homodimers in a water-soluble, self-assembled supramolecular host.” Proc. Nat. Acad. Sci. U.S.A. 2009, 106, 10438-10443