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More than DKK 23 million (USD 3.3 million) to researchers from MBG from the Independent Research Fund Denmark

The Independent Research Fund Denmark (DFF) - Nature and Universe - grants DKK 23.4 million to seven researchers at the Department of Molecular Biology and Genetics.

2020.05.18 | Lisbeth Heilesen

The following researchers from MBG have received a grant from DFF:

  • Gregers Rom Andersen – DKK 2.876.575 for the project “Structural dissection of the IgE-FceRI interaction”
  • Ditlev Egeskov Brodersen – DKK 2.879.999 for the project “Understanding the molecular basis of NAD+-depleting toxins in bacteria”
  • Jan Johannes Enghild – DKK 2.840.287 for the project “Determining the molecular mechanisms underlying the conformational collapse of alpha macroglobulin protease inhibitors”
  • Rune Hartmann – DKK 2.873.618 for the project “Characterisation of a novel antiviral pathway in Drosophila melanogaster”
  • Charlotte Rohde Knudsen – DKK 2.877.843 for the project “Single-molecule studies of how amino acids are accurately selected during protein synthesis on the ribosome”
  • Ulf Andersson Vang Ørom – DKK 2.880.000 for the project “miR22HG - from microRNA to enhancer”
  • Bjørn Panyella Pedersen – DKK 6.191.260 for the project Molecular mechanisms of sterol uptake

Gregers Rom Andersen – DKK 2.876.575

Structural dissection of the IgE-FceRI interaction

Immunoglobulin E (IgE) is the antibody responsible for allergic reactions. We want to address how binding of IgE-allergen complexes to the transmembrane receptor FcεRI induces allergic responses. We will take advantage of that human IgE is a rigid antibody both free and when bound to the receptor. We will purify the very tight human 290 kDa IgE-FceRI complex and use cryoEM for structure determination of the complex. The project will considerably improve our understanding of diseases involving allergen/IgE/receptor complexes and form the basis for future therapeutic targeting of the IgE-FcεRI axis.


Ditlev Egeskov Brodersen – DKK 2.879.999

Understanding the molecular basis of NAD+-depleting toxins in bacteria

Most bacteria use sophisticated molecular mechanisms to survive periods of stress, including nutrient deprivation and for pathogens, exposure to antibiotics. These mechanisms include expression of a set of small intracellular toxins, in the form of so-called toxin-antitoxin systems, that allow cells to quickly down-regulate their metabolism, often through specific degradation of stable RNA species. Intriguingly, recent discoveries have shown that some bacteria perturb their own metabolism using toxins that deplete cellular NAD+, likely in a last-ditch attempt to survive stressful situations. Despite recent progress in this field, we still know little about the precise mechanism of action of the toxins, which are widespread in bacteria. In this project, we aim to obtain detailed insights into catalysis and regulation by DNA-binding of a Xre-RES toxin-antitoxin complex from Pseudomonas. Knowledge about the underlying mechanisms will help development of new antibiotics in the future.


Jan Johannes Enghild – DKK 2.840.287

Determining the molecular mechanisms underlying the conformational collapse of alpha macroglobulin protease inhibitors

Alpha macroglobulins (aMs) are one of the most successful protease inhibitor families and have been identified in organisms from bacteria to humans. The reason for the ubiquitous distribution is most likely the ability to inhibit (almost) all proteases irrespective of catalytic mechanism or specificity. This is unique in nature as other protease inhibitor families employ a "lock and key" active site-directed approach and are thus only inhibits members of one mechanistic class of proteases. This astonishing ability to inhibit all proteases is the result of a unique inhibitory mechanism that involves trapping the protease within the aM molecule following cleavage of a peptide bond within an exposed stretch of amino acid residues referred to as the bait-region. However, a molecular understanding of how aM's harbor - and upon cleavage releases the mechanical forces required to accomplish this task, is not understood and is the motivation for this application.


Characterisation of a novel antiviral pathway in Drosophila melanogaster

Rune Hartmann – DKK 2.873.618 

We recently demonstrated that the Drosophila orthologue of STING orchestrates an innate immune response to virus infection. Our discovery suggests that the STING pathway represents one of the evolutionary oldest antiviral defence systems. Interestingly, where mammalian STING protect against infection with DNA viruses, Drosophila STING protects flies against RNA viruses. This opens the question: What are the upstream events leading to activation of Drosophila STING? We have identified two cGAS-like proteins in Drosophila and our preliminary data show that they can activate STING upon infection with an RNA virus. Using classical enzymatic assays as well as pull down and next generation sequencing, we will identify the exact nature of the activator of the cGAS-like proteins. Furthermore, we will characterise what kind of CDN they produce using a combination of enzymatic assays and NMR.


Charlotte Rohde Knudsen – DKK 2.877.843 

Single-molecule studies of how amino acids are accurately selected during protein synthesis on the ribosome

During translation of the genetic message, elongation factor EF-Tu transports amino acids to the ribosome, and helps securing that the amino acids are correctly selected. Despite decades of studies, the underlying mechanism remains poorly understood. We will use an advanced single-molecule technique, polarized total internal reflection fluorescence microscopy (polTIRF), in collaboration with Prof. Yale Goldman at University of Pennsylvania, to compare the dynamic behaviour of EF-Tu during correct and incorrect decoding. EF-Tu mutants will be labelled with a bifunctional, fluorescent probe at strategic positions, and active, labelled EF-Tu molecules will be studied during their interaction with ribosomes. The powerful but underutilized polTIRF technique delivers spatial and kinetic information unavailable to bulk experiments and structural studies. Accurate protein synthesis is of medical and biotechnological relevance, and these fields may benefit from the results of this project.


Ulf Andersson Vang Ørom – DKK 2.880.000

miR22HG - from microRNA to enhancer

miRNAs are small regulatory RNAs mediating posttranscriptional control of gene expression in the cytoplasm. Long non-coding RNAs often control gene expression in the nucleus. miRNAs are transcribed as long non-coding primary transcripts (pri-miRNA) that undergo a multistep biogenesis pathway on their way to mature miRNAs. My laboratory has developed the first approach to transcriptome-wide determination of endogenous pri-miRNAs and used it to identify transcripts with significant changes in processing efficiency. One of the identified pri-miRNAs, miR22HG, shows complete change of transcript fate during differentiation and development, going from encoding a miRNA to producing a long non-coding RNA. In this proposal we aim to identify the molecular mechanism responsible for this change of transcript function and the biological impact of changing transcript class during differentiation and development.


Bjørn Panyella Pedersen – DKK 6.191.260 for the project Molecular mechanisms of sterol uptake

Read the separate article about Bjørn Panyella Pedersen’s research


 

See a list of all recipients of a grant from the Independent Research Fund Denmark

The article was based on a media release from the Independent Research Fund Danmark

Grant