The current list contains projects posted under Programa Ciência sem Fronteiras by the Section for Biomolecular Sciences at the Department of Biology.

The program is only open to Brazilian nationals.

3rd august 2016: Unfortunately, the program has been temporarily suspended by the brazillian government.


Section for Biomolecular Sciences, Dept of Biology, University of Copenhagen:

Protein Design

The emerging ability to predict protein structure from sequence opens the intriguing possibility of approaching the inverse problem of finding an amino acid sequence compatible with a predefined structure. Considering the diverse functional properties of proteins, the theoretical and practical implications of being able to build protein structure, at will, are tremendous.

Contemporary tools of chemistry and molecular biology allow protein sequences to be routinely generated from synthetic DNA and recent advances in the computational methods have made it possible to design completely new proteins with specific and novel structures. We are using bioinformatic and genetic tools to establish enhanced methods for protein design based on simple templates. We are currently testing multiple such designs and several projects are available within the area of protein design and selection.

For more information, please contact: Professor Jakob R. Winther (jrwinther@bio.ku.dk);http://www.bio.ku.dk/bms/jrw


Section for Biomolecular Sciences, Dept of Biology, University of Copenhagen:

Intracellular redox sensing

Redox potential is strictly controlled in different compartments of all living cells. Changes in cellular redox state are often associated with pathological conditions in humans, such as cancer and neurodegenerative diseases. The nature and quantity of redox active components, however, as well as their localization in healthy and diseased cells remain major unanswered questions in redox biology. One of the ways to address this problem is genetically encoded redox sensors that allow for non-invasive observation of redox components in various compartments of the cell. For example, GFP based redox sensors have changed our understanding of intracellular redox metabolism. These sensors have a unique specificity towards glutathione, which is commonly regarded as a key player in cellular redox homeostasis. We have recently determined that protein thiols globally constitute an equally important redox pool in cells, an aspect of redox metabolism which is not addressed by these sensors.

In the project proposed we are developing new sensors for intracellular redox sensing based on GFP and other proteins which target other redox systems than those based on glutathione.

Relevant references:

For more information, please contact: Professor Jakob R. Winther (jrwinther@bio.ku.dk); http://www.bio.ku.dk/bms/jrw


Section for Biomolecular Sciences, Dept of Biology, University of Copenhagen:

Endoplasmic reticulum-associated degradation (ERAD) of disease-causing mutants of plasma membrane proteins

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) poses a serious threat to eukaryotic cells and is associated with serious diseases. Therefore, misfolded ER proteins are retrotranslocated to the cytosol where they are degraded by the proteasome following poly-ubiquitination. This process is termed ER-associated degradation (ERAD).

In our lab, we work on characterizing various protein components of the ERAD system in mammalian cells. Thus, we investigate their cell biological and biochemical functions in the degradation of specific ERAD substrates. In this project, we will use RNA interference (RNAi) screening in mammalian cells to identify ERAD components involved in the degradation of plasma membrane proteins that carry disease-causing mutations, which result in misfolding. Further on, we will characterize the cell biological function of the identified components in ERAD. The aims of this project is to gain a better fundamental understanding of the ERAD process in mammalian cells, and - in the longer term - help develop a strategy to cure serious diseases caused by protein misfolding.

References:

  • Christensen LC, et al. (2012) The human selenoprotein VCP-interacting membrane protein (VIMP) is non-globular and harbors a reductase function in an intrinsically disordered region. J. Biol. Chem., 287, 26388-26399.
  • Riemer, J., et al. (2009) A luminal flavoprotein in endoplasmic reticulum-associated degradation. Proc. Natl. Acad. Sci. USA, 106, 14831-14836.

For more information, please contact: Associate Professor Lars Ellgaard (lellgaard@bio.ku.dk); http://www.bio.ku.dk/bms/le


Section for Biomolecular Sciences, Dept of Biology, University of Copenhagen:

The cellular response to oxidative stress in the mammalian endoplasmic reticulum

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) poses a serious threat to eukaryotic cells and is associated with serious diseases. The unfolded protein response (UPR) is a coordinated transcriptional and translational program that is initiated under conditions of ER stress that lead to protein misfolding. The UPR seeks to restore normal cellular conditions, for instance by upregulating ER chaperones while also increasing the cellular capacity to degrade misfolded ER proteins.

By overexpressing a deregulated mutant of the ER oxidase called Ero1alpha, we have recently created stable transfectants of HEK293 cells that experience ER hyperoxidation. This in turn upregulates a wide variety of known UPR markers. In addition, a number of proteins previously not associated with the UPR are upregulated under these conditions. In this project, we will characterize the cellular function of these proteins in order to shed light on previously unexplored aspects of the mammalian UPR. In particular, we will focus our attention on how the upregulation of these proteins might help restore ER redox homeostasis. Thus, we hope to gain fundamental new insight into the mechanisms of ER redox regulation.

References:

  • Hansen HG et al. (2012) Hyperactivity of the Ero1α oxidase elicits endoplasmic reticulum stress but no broad antioxidant response. J. Biol. Chem., 287, 39513-39523.
  • Bulleid, N. J. and Ellgaard, L. (2011) Multiple ways to make disulfides. TiBS, 36, 485-492
  • Appenzeller-Herzog, C. et al. (2010) Disulfide production by Ero1α-PDI relay is rapid and effectively regulated. EMBO J., 29, 3318-3329.

For more information, please contact: Associate Professor Lars Ellgaard (lellgaard@bio.ku.dk); http://www.bio.ku.dk/bms/le


Section for Biomolecular Sciences, Dept of Biology, University of Copenhagen:

Characterization of novel components of the ubiquitin-proteasome system

In nature, cells are regularly challenged by environmental and physiological stress conditions which may lead to protein misfolding. If misfolded proteins are allowed to linger, they invariably aggregate in larger structures that are toxic to cells. Since a hallmark of many neurodegenerative disorders, including Parkinson’s and Alzheimer’s disease, is the presence of insoluble protein aggregates in the affected cells and tissues, these diseases are most likely, at least in part, a result of an inefficient cellular clearance of misfolded proteins. To cope with the presence of partially denatured proteins, cells have developed two alternative pathways: either the proteins are shielded from aggregation and refolded to the native state by molecular chaperones or, if the native state is unattainable, targeted for degradation. In eukaryotic cells, the majority of intracellular proteins are degraded via the ubiquitin-proteasome system (UPS). This system depends on a cascade of three enzymes termed E1, E2 and E3 that conjugate ubiquitin to specific target proteins. Subsequently, the proteins, which have been marked with polyubiquitin, are transferred to the 26S proteasome, a 3 MDa proteolytic particle found in the nucleus and cytosol of all eukaryotic cells. At the 26S proteasome, deubiquitylating enzymes release the ubiquitin chains while the substrate is degraded into shorter peptides.

This project focuses on the characterization of a group of novel proteins that is involved in the UPS. The work will comprise a number of molecular biological techniques using yeast and mammalian cells in tissue culture.

To undertake this project, the student must have a strong background (Master’s level) in biochemistry or a related field, and experience with molecular cloning, recombinant proteins and basic cell biology. In addition, some experience with yeast genetics will be an advantage. Related projects are also available at the Post Doc level.

References

  • Poulsen EG, Steinhauer C, Lees M, Lauridsen AM, Ellgaard L, Hartmann-Petersen R (2012) HUWE1 and TRIP12 collaborate in degradation of ubiquitin-fusion proteins and misframed ubiquitin. PLoS One 7:e50548.
  • Andersen KM, Madsen L, Prag S, Johnsen AH, Semple CA, Hendil KB, Hartmann-Petersen R (2009) Thioredoxin Txnl1/TRP32 is a redox-active cofactor of the 26 S proteasome. J. Biol. Chem. 284:15246-15254.

For more information, please contact: Associate Professor Rasmus Hartmann-Petersen, (rhpetersen@bio.ku.dk); http://www.bio.ku.dk/bms/rhp


Postdoc or PhD-position at Biomolecular Sciences, Dept of Biology, University of Copenhagen:

Quorum sensing control of phage-bacterial interactions

The goal of the overall project is to clarify the role of bacterial cell-cell signaling, called quorum sensing, in shaping the interactions between bacteria and the viruses that prey on them, bacteriophages (phages). The predation pressure from phages is a key determinator of the size and composition of bacterial populations. Therefore, an increased understanding of the factors that determine the outcome of phage-bacteria encounters will be important in any context where the goal is to control the growth of a microbial population including, for example, the treatment of bacterial infections, development of effective probiotics, production of cultured dairy products, or manipulation of the human microbiome to prevent or treat life-style diseases.

Recent evidence from our laboratory shows that the model bacterium Escherichia coli K-12 uses quorum sensing to regulate its anti-phage defense mechanisms based on the cell density of the population. The current project will focus on the effects of cell-cell signaling from the phage’s point of view. Phages have evolved to incorporate sensory inputs into the genetic switches that govern their infection strategies. As bacterial cell-cell signaling provides clues about the density of potential host cells, phages could benefit from ‘eavesdropping’ on the signals received by the host cell they reside in, to produce and release progeny phages specifically when new host cells are abundant. We will identify naturally occurring phages that use quorum sensing to control their development, and characterize the underlying molecular mechanism and the physiological function of the quorum sensing regulation.

The position is open to applicants seeking both the PhD-degree (3 years) and postdoc experience (2 years). Applicants with laboratory experience in microbiology, and particularly phage biology, will be preferred.

Relevant reference: Høyland-Kroghsbo NM, Mærkedahl RB, Svenningsen SL. 2013. A quorum-sensing-induced bacteriophage defense mechanism. mBio 4(1):e00362-12. doi:10.1128/mBio.00362-12.

For more information, please contact: Associate Professor Sine Lo Svenningsen (SLS@bio.ku.dk); http://www.bio.ku.dk/bms/sls.


PhD position at Biomolecular Sciences, Department of Biology, University of Copenhagen:

Towards a Predictive Understanding of Cancer Mutations

Mutations can either be inherited or arise spontaneously and underlie the formation of many cancers. We are working towards developing a predictive understanding of the effect of such mutations on the structure, stability, dynamics and function of proteins. The current project will use a broad range of computational methods, ranging from bioinformatics to molecular simulations, to study the effect of mutations involved in colon cancer. The current project constitutes the computational component of a larger project that involves collaborations both with biochemists, molecular biologists and clinicians.

The project will be performed in the Lindorff-Larsen group in the Structural Biology and NMR Laboratory (www.bio.ku.dk/sbinlab/), in which we use a broad range of computational methods to study the structure, function, and dynamics of proteins. These studies are in general carried out in close collaboration with experimental studies, and a strong component of our research is the tight interconnection between theory and experiments. Our research group provides a dynamic and international environment, with a strong track record in utilizing computational methods to study biological problems.

To undertake this project, the candidate should have a strong background in computational studies of proteins, preferably also having a good understanding of protein biochemistry.

For more information, please contact: Associate Professor Kresten Lindorff-Larsen (lindorff @ bio.ku.dk);http://www.bio.ku.dk/bms/kll


PhD position at Biomolecular Sciences, Department of Biology, University of Copenhagen:

Structures of Protein Complexes Using Biochemical Data

The ability to determine the three-dimensional structures of proteins has been an important development in protein science, and in our ability to understand and exploit the function of proteins. Proteins do, however, rarely function isolated from one another, but are instead often found in a number of macromolecular complexes. Our ability to determine the structures of such complex structures is, however, hampered both by technical difficulties and the combinatorial nature of the many complexes proteins can form. The project proposed here suggests a new strategy to determine structures of biological complexes more easily and efficiently. The approach is based on a combination of state-of-the art computational methods with an efficient approach to obtain biochemical data. The research project will both involve a computational and experimental component.

The project will be performed in the Lindorff-Larsen group in the Structural Biology and NMR Laboratory (www.bio.ku.dk/sbinlab/), in which we use a broad range of computational methods to study the structure, function, and dynamics of proteins. These studies are in general carried out in close collaboration with experimental studies, and a strong component of our research is the tight interconnection between theory and experiments. Our research group provides a dynamic and international environment, with a strong track record in utilizing computational methods to study biological problems.

To undertake this project, the candidate should have a strong background in experimental protein biochemistry or biophysics, preferably also having some experience in computational biology.

For more information, please contact: Associate Professor Kresten Lindorff-Larsen (lindorff @ bio.ku.dk); http://www.bio.ku.dk/bms/kll


PhD position at Biomolecular Sciences, Department of Biology, University of Copenhagen:

New Computational Methods to Improve the Use of NMR in the Study of Large Proteins

NMR spectroscopy provides access to both structural and dynamical information in proteins and other macromolecules. Due to technical limitations it has, however, traditionally been difficult to use NMR to study larger proteins. The current project aims to make it possible to study both the structure and dynamics of larger proteins by combining a broad range of experimental data with state-of-the-art computational methods. By developing new and innovative methods for data-integration and molecular simulations, the project aims to provide a robust and general framework to utilize NMR to study protein structure and dynamics.

The project will be performed in the Lindorff-Larsen group in the Structural Biology and NMR Laboratory (www.bio.ku.dk/sbinlab/), in which we use a broad range of computational methods to study the structure, function, and dynamics of proteins. These studies are in general carried out in close collaboration with experimental studies, and a strong component of our research is the tight interconnection between theory and experiments. Our research group provides a dynamic and international environment, with a strong track record in utilizing computational methods to study biological problems.

To undertake this project, the candidate should have a strong background in experimental protein biochemistry or biophysics, preferably also having some experience in computational biology.

For more information, please contact: Associate Professor Kresten Lindorff-Larsen (lindorff @ bio.ku.dk); http://www.bio.ku.dk/bms/kll


PhD position at Biomolecular Sciences, Dept of Biology, University of Copenhagen:

Networks of transcription factors involved in abiotic stress responses

 Transcription factors (TFs) are master regulators of abiotic stress responses in plants. Genetic engineering of a single TF may be sufficient to enhance stress tolerance in plants, making these TFs attractive targets of engineering. Many TFs are hubs, which have many partner proteins, in dynamic networks, and have extended regions with protein intrinsic disorder, referring to their lack of a fixed tertiary structure.

To improve the platform for engineering the project will address the following questions for relevant TFs: 1) What are their target genes and gene regulatory networks? 2) How do they function in networks and what is the role of protein intrinsic disorder in these networks? This involves the use of the following technologies: RNA sequencing, chromatin immunoprecipitation (ChIP), protein binding microarrays (PBMs), production of recombinant proteins, biophysical protein characterization, and applied bioinformatics.

References:

  • Lindemose, S., O'Shea, and Skriver, K. (2013) Forward genetics and protein structure/function relationships of transcription factors involved in abiotic stress. Int. J. Mol. Sci. 14, 5842-5878
  • Kragelund, B.B., Jensen, M.K., and Skriver, K. (2012) Order by disorder in plant signaling. Trends Plant Sci. 17, 625-632
  • Kjaersgaard, T., Jensen, M.K., Christiansen, M.W., Gregersen, P. Kragelund, BB., and Skriver, K. (2011) Senescence induced NAC transcription factor interacts with Radical Induced Cell Death1 hub through disordered regulatory domain. J. Biol. Chem. 286, 35418-35429
  • Jensen, M. K., Kjaersgaard, T., Nielsen, M. M., Galberg, P., Petersen, K., O’Shea, C., and Skriver, K. (2010) The Arabidopsis thaliana NAC transcription factor family: structure-function relationships and determinants of ANAC019 stress signalling. Biochem. J. 462, 183-196.

For more information, please contact: Professor MSO Karen Skriver (kskriver@bio.ku.dk); http://www.bio.ku.dk/bms/ks