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Horizon doorbraakprojecten

Horizon Breakthrough Projects
Granted Projects- Seventh Call


Bacteria on Sex Hormones
Dr. R (Robert) van der Geize (m), 30-05-1970, University of Groningen - Department of
Microbiology
Estrogens are highly bioactive steroid hormones mainly entering the environment via waste water
treatment effluents, which is of major environmental concern. Estrogens have immune-modulating
functions and have been proposed to play a role in resistance to bacterial infections. Transcriptome
analysis will be performed to elucidate the enigmatic microbial estrogen catabolic pathway.

Druggable DUbs in trypanosomes
Dr. B. (Boris) Rodenko (m), 5-2-1975, Netherlands Cancer Institute - Division of Cell Biology
Sleeping sickness threatens millions of people in Africa and causes about 70,000 deaths each year.
Also livestock suffers from this disease, which frustrates local economy. Current drugs are difficult to
administer, have severe side effects and drug resistance is emerging rapidly. Clearly, there is an urgent
need for new and safe medication. Sleeping sickness is caused by the parasite Trypanosoma brucei and
in this project we will explore a class of proteins, so called deubiquitinating enzymes, as new targets for
therapeutic intervention.

Metabolite imaging using FRET-based sensors
Dr. S.F.J. (Stan) van de Graaf (m), 18-08-1977, University Medical Centre Utrecht -
Metabolic and Endocrine diseases
Better insight into metabolite profiles of tissue, body fluids and cells is essential for our understanding
of human (patho)physiology. Nature has devised proteins that can sense metabolites in a sensitive and
specific manner. In this project researchers utilize these proteins to create sensors that enable sensitive,
dynamic measurement of specific metabolites at single cell, or even subcellular resolution.
Targeted, quantitative, multiplex imaging mass spectrometry
Dr. L.A. (Liam) McDonnell (m), 4-6-1975, Leiden University Medical Centre - Department of
Parasitology, Biomolecular Mass Spectrometry Unit
Modern biomolecular analytical techniques have identified a large number of proteins that are associated
with specific diseases, so called biomarkers. Conservative estimates for the three most common cancers
in the Netherlands are breast cancer (37), colorectal cancer (65), and prostate cancer (36).
Simultaneous analysis of just 4 breast cancer biomarkers has demonstrated improved diagnostic
capabilities, so developing tests incorporating many biomarkers could lead to improved patient diagnosis
for a variety of diseases. Simultaneous (multiplex) imaging of multiples biomarker could also help
illuminate the roles of the different cell types often found in a tumour. Here we will establish the
capabilities of a new method, based on mass spectrometry, for quantitative multiplex imaging of protein
biomarkers, which has the potential to allow multiplex analysis of >30 biomarker proteins.

Healthy brains as treasure trove of ADHD genes
Dr. A. (Alejandro) Arias-Vasquez (m), 22-6-1975, Radboud University Nijmegen Medical
Centre - Departments of Psychiatry & Human Genetics
Abnormalities of the volume of brain structures have been documented in many psychiatric disorders and
genetic factors explain a considerable part of the variability of these structures. In this project we want
to test the hypothesis that the identification of common genetic variants (single nucleotide
polymorphisms [SNPs] and copy number variants [CNVs]) related to the change in the volume of brain
structures in healthy individuals can serve as a powerful tool to identify risk factors for psychiatric
disorders, in this case Attention Deficit/Hyperactivity Disorder (ADHD). In order to accomplish this aim,
we will first assess the association between SNPs/CNVs and the volume of brain structures as estimated
by Magnetic Resonance Imaging (MRI) in a population of 1000 healthy participants of the Brain Imaging
Genetics (BIG) study. Second, we will test if the SNPs/CNVs associated with brain volumes (found in step
1) are associated with the risk for ADHD using the information provided by ADHD studies performed in
children and adults and, third, we will evaluate if the variants associated with brain volumes and ADHD
risk have an effect on brain function.

Massive parallel sequencing for extreme genomes
Dr. R. (Richárd) Bartfai (m), 23-5-1975 Radboud University Nijmegen
Deciphering genomes has been a major challenge to biologist for decades. The current development in
sequencing technologies revolutionized genome research, but has its limitations especially if the
sequence composition is unusual. The genome of the human malaria parasite provides one such example
of an extreme genome that severely hinders its exploration and exploitation. This project aims at the
adaptation of the deep sequencing technology to extreme genomes that will enable the investigation of
regulatory mechanism that govern parasite growth and pathogenicity. Knowledge and technological
advances gained during the project could ultimately help us to identify new drug candidates and combat
this and possible other devastating diseases.
A promoter resource to study the effect of genome duplication on regulatory sequences
Dr. U.G. (Ulrike) Jacobi (f), 9-3-1979, Radboud University Nijmegen, Nijmegen Centre
for Molecular Life Sciences
The clawed frog Xenopus is an animal model that enables researchers to study diseases and complex
processes in whole organisms and can be used to mimic the situation in humans. Strikingly, one member
of the Xenopus family, Xenopus laevis has doubled its genome during evolution which makes it also an
interesting model for evolutionary processes. This research project aims to identify DNA sequences that
play an important role in switching genes on and off. The obtained regulatory sequences enable
researchers to apply genomic techniques and will be analyzed to reveal new insight into the effect of
genome duplication. Additionally, the identified regulatory sequences can be used by all researchers
working with Xenopus laevis.

Using zebrafish to explore miRNAs as drug targets for bone related diseases.
Dr. R.F. (René) Ketting (m), 19-05-1971, Hubrecht Institute
In our aging society, bone-related diseases represent an ever-increasing medical problem, for which few
effective treatments are available. We will explore to what extent small RNA molecules, also named
microRNAs, are effective targets for the development of new drugs that can be used to treat bone related
diseases, as microRNAs have been shown to be relatively easy and effective drug targets. We will identify
the microRNAs that are present in the cells that make bone, and what their effects are on the functions
of these cells. Based on these results we will judge which ones might be useful as novel drug targets. To
achieve this, we will use zebrafish embryos as a model, because gene function, including microRNA
function, can be easily manipulated and bone development can be easily followed in living embryos.
A chemical emergency switch for plants
Dr. C.S. (Christa) Testerink (f), 20-10-1973, UvA University of Amsterdam, Swammerdam
Institute for Life Sciences (SILS), Mass spectrometry of Macromolecules
Phosphatidic acid (PA) is an important signaling lipid. In plants, it is essential for survival under adverse
conditions. In this breakthrough project, we will engineer a chemical switch to make PA at will in plant
cells. We will then turn on the switch and investigate the proteome-wide consequences. The ultimate
goal is to find protein targets that can be exploited in plant breeding to enhance stress tolerance.

An inflammasome genome screen to detect novel disease genes in hereditary
autoinflammatory disorders
Dr. M.E. (Marielle) Van Gijn (f), 21-2-1970, University Medical Centre Utrecht - Division
of Biomedical Genetics
For a large percentage of the patients with hereditary autoinflammatory disorders, such as Familial
Mediterranean Fever and Muckle-Wells syndrome, the underlying cause of the disorder remains
unexplained. This raises the question which gene(s) are responsible for these disorders. This project will
screen 120 potential disease related genes in these patients for disease associated mutations using state
of the art techniques. The identification of genes, which are causing the above mentioned diseases will
not only help diagnostics and the development of future therapies but has also implications for other
multifactorial autoinflammatory disorders.
Bacterial virulence gene discovery using phage display technology
Dr. P.J.A. (Pieter-Jan) Haas (m), 20-8-1974, University Medical Center Utrecht
- Department of Medical Microbiology
Pathogenic bacteria use different ways to evade the host immune defenses through the production of
immune evasion molecules in order to cause colonization and infection. Identifying these immune
evasion molecules is a time consuming and inefficient process. In this project we functionally select
secreted bacterial proteins using the power of phage display technology. This novel approach greatly
enhances the identification of these immune evasion molecules. Understanding bacterial immune evasion
will lead to better understanding of infection and inflammation and novel strategies in the treatment of
infectious and inflammatory diseases.

The tomato RNA degradome in fruit development and domestication.
Dr. R.B. (Rumyana) Karlova (f), 13-4-1978, Wageningen University and Research Centre -
Department of Molecular Biology
Tomato is an important crop as well as a model system for studying fleshy fruits in plants. During the
domestication process beneficial alleles underlying yield and quality of the cultivated plant compared to
its wild relatives were selected. Through domestication, research and breeding activities that were
implemented by scientist and breeders worldwide, modern tomato varieties have been developed in a
variety of shapes, colors and sizes. In this project we would like to study the role of small regulatory
RNAs and their conservation during the domestication process by comparing different wild species and
natural mutants with a focus on fruit ripening

A novel screening method to identify human adipokine-receptor interactions
Dr. J.W. (Johan) Renes (m), 25-11-1971, Maastricht University, Faculty of Health, Medicine
and Life Sciences - Human Biology
Aim of this project is the establishment of a novel method to detect interactions between secreted
cellular proteins from one cell and receptor proteins on other cells. Fat cell secreted proteins (adipokines)
are chosen as a model since they play a major role in the development of obesity-related disorders by
targeting other non-fat tissues like liver and muscle. Here, liver cells are chosen as target cells. Since
this novel method is not restricted to adipokines and liver cells, but applicable to any secreted protein
and target cell, it will open a new area in explorative research with respect to inter-cellular
communication.

Dissecting the fruit formation transcriptional regulatory network
Dr. ir. R.G.H. (Richard) Immink (m), 13-3-1973, Wageningen University and Research Centre -
Plant Sciences Group
Fruits are one of the major sources of our daily food. Understanding how genes orchestrate fruit
formation is essential for optimizing fruit production. In this research novel genomic tools will be
developed to decipher the function of individual genes at different stages of fruit development.

BAC TransgeneOmics-based Systems Microscopy for Predictive Toxicology
Dr. Ir. B.H.A. (Bram) Herpers (m), 04-04-1979, Leiden University, LACDR - Division of
Toxicology
Safety assessment of new drugs relies on end-point measurements by tradition. Toxicity is a time-
dependent multi-step process in which proteins react by changing their intracellular location. By tagging
these responsive proteins with fluorescent tags in their natural environment, the researcher aims to
develop microscopy tools that can predict drug safety in vitro.

miRNA expression as a new tool for sepsis diagnosis in Intensive Care
Dr. C.W. (Catharina) Wieland (f), 7-3-1978, Academic Medical Centre Amsterdam (AMC)
The reaction of the body to infection (sepsis) is still a prominent cause of morbidity and mortality in the
intensive care unit. New tools that can distinguish between critically ill patients and patients with sepsis
are necessary to avoid inadequate treatment. Within this project, we will search for specific miRNAs in
whole blood that discriminate between critically ill patients and sepsis patients. Whole blood is easy to
obtain and no further time consuming purifications are necessary. This approach could provide a first
step to a fast and easy miRNA based diagnostic tool for sepsis.

Analyses of the role of small virus-derived RNAs in human antiviral immune responses
Dr. P.C.J. (Joost) Haasnoot (m), 20-10-1971, Academic Medical Centre Amsterdam (AMC),
Centre for Infection and Immunity Amsterdam (CINIMA), Laboratory of Experimental
Virology, Department of Medical Microbiology
All organisms have specific mechanisms to protect themselves against invading viruses. In plants, insects
and nematodes a special mechanism called RNA interference (RNAi) plays an important role in antiviral
defenses. Although RNAi also exists in mammals, it is unclear whether it has an antiviral function. In this
project we will study the role of RNAi in controlling HIV-1 replication in human cells. For this we will use
novel highly sensitive sequencing technology.
Discovery of stem cell markers in the regenerating flatworm Macrostomum lignano
Dr. E. (Eugene) Berezikov (m), 7-7-1975, Hubrecht Institute - Generegulation
Stem cells hold great promise for regenerative medicine and various disease therapies, and have
attracted a lot of research interest in recent years. Due to technical reasons some fundamental questions
concerning stem cell biology can be best addressed in invertebrate experimental model organisms like
flatworms, which have an astonishing regeneration capacity. Regeneration in flatworms is facilitated by a
population of stem cells called neoblasts, which are the only proliferating cells within the organism and
perform a crucial role during development, regeneration and tissue homeostasis. In the proposed project
I aim to use next-generation sequencing technologies to identify genes that are specifically expressed in
the neoblasts of the free-living flatworm Macrostomum lignano, and thus could have relevant roles in
regulation of neoblast dynamics. Identification and verification of these stem cell-regulating genes should
form a fundamental toolbox for further research on how stem cells are maintained in an undifferentiated
state or induced to go into differentiation using M. lignano as a model organism.
Conditional and rapid inactivation of nuclear factor functions by 3A technology (Advanced-
Anchor-Away)
Dr. E. (Eric) Soler (m), 14-11-1976, Erasmus MC - Department of Cell biology
Transcription Factors (TFs) are nuclear proteins controlling gene regulatory networks, governing cellular
identity, proliferation and differentiation. We propose to analyze the roles specific TF play on gene
expression by developing a new technology allowing very fast and inducible TF inactivation (within
minutes) through their sequestration in the cytoplasm ("spatial knock-out"). Due to its speed, this
system (called 3A) will allow for the first time to dissect the very early and specific effects TF play on
gene expression.
Ultra-high throughput analysis of insertional mutations to study collaborating cancer genes
and genetic networks in mouse tumors
Dr. J.M.M. (Jos) Jonkers (m), 16-5-1965, Netherlands Cancer Institute - Molecular Biology
Cancer is a genetic disease caused by accumulation of mutations in oncogenes and tumor suppressor
genes. Identification of these cancer-related mutations may yield novel targets for anti-cancer
therapeutics. Retroviral or transposon-based insertional mutagenesis screens in mice are an effective
way to identify large numbers of cancer-related mutations. We will use massively parallel sequencing
methods for ultrahigh-throughput analysis of insertional mutations in mouse models of breast cancer.
Our method enables unbiased and quantitative analysis of clonal and subclonal mutations in genetically
heterogeneous tumors and facilitates identification of co-occurring mutations.

Functional genomics of antiviral defense in insects
Dr. ir. R.P. (Ronald) van Rij (m), 17-09-1972, Radboud University Nijmegen Medical Centre -
Medical Microbiology
Humans and other vertebrate animals have a sophisticated and complex immune system for the defense
against pathogens, such as viruses. Invertebrate animals are also infected by viruses, yet, little is known
about the invertebrate immune system. Using the fruit fly, Drosophila melanogaster, as a model
organism, the researchers will identify novel genes for the defense against viruses in insects.
Autoimmune disorders looking: for common grounds using uncommon methods.
Dr. M.J.H. (Marieke) Coenen (f), 9-10-1975, Radboud University Nijmegen Medical Centre -
Department of Human Genetics
Autoimmune disorders are caused by the dysregulation of the immune system resulting in destruction of
normal tissue. This common mechanism suggests the existence of shared risk factors for different
autoimmune disorders. Using a novel method (Bayesian Variable Selection Method) we will identify
shared genes and pathways underlying four autoimmune diseases: rheumatoid arthritis, Crohn‟s disease,
ulcerative colitis and psoriasis.

State-of-the art sequencing technology to identify genes for hearing loss in the Dutch
population
Dr. ing. M. (Margit) Schraders (f), 9-12-1978, Radboud University Nijmegen Medical Centre -
Department of Human Genetics

Hearing loss is the most common sensory disorder and has a tremendous negative impact on the quality
of life in our complex society which relies on rapid communication. Defects in more than 100 different
genes can cause early onset hearing loss, however, less than one third of the causative genes have been
identified. This project aims at the identification of the genes that are involved in early onset hereditary
hearing loss in the Dutch population with a novel technology for DNA sequencing. The results will be
translated into patient care and for many patients and families the question on the cause of the hearing
loss can be answered as a result of this study and follow-up studies.

Identifying biomarkers for immune-related diseases using genome-wide ribosomal-associated
RNA expression profiles
Dr. C.C. (Cleo) van Diemen (m), 13-11-1979, University Medical Centre Groningen - Genetics
The diagnosis of diseases can be difficult because symptoms may be non-specific and because many
environmental and genetic factors can influence the disease. It would be useful to have an easily
assessable marker, such as a protein in blood, for each disease (so-called biomarkers) to diagnose and
monitor patients. Every protein is generated through the process of translation of an mRNA molecule by
ribosomes, with the number of mRNA molecules and how much mRNA is translated into protein being
tightly regulated. We think that differences in the number of mRNA molecules bound to ribosomes may
well reflect the amount of protein produced and thus may reflect the disease status of a patient. In this
project we aim to find new biomarkers for patients with two types of inflammatory bowel disease
(Crohn‟s disease and ulcerative colitis) as a proof-of-principle by assessing the levels of ribosome-
associated mRNA.

SQIL, a new method to measure the impact of gene acquisition on bacterial evolution
Dr. M. (Marian) Llamas Lorente (f), 13-11-1973, VU Medical Centre - Department of Medical
Microbiology

Bacteria multiply asexually by binary fission, which implicates that bacteria are in fact clonal. However,
bacteria also show horizontal gene transfer, a process by which genes from another strain or another
species are acquired. This process plays an important role in the evolution of new bacterial species,
including new bacterial pathogens. In this project we will develop a new tool which will allow to measure
exactly the effect of horizontal gene transfer on a genome-wide scale. This tool will be used to study the
evolution of pathogenic bacteria and to identify new targets for antibiotics.
High-throughput miRNA-mRNA target identification
Dr. P.A.C. (Peter-Bram) 't Hoen (m) ,17-1-1975, Leiden University Medical Centre, Centre for
Human and Clinical Genetics
MicroRNAs (miRNA) are important regulators of gene expression in biological systems by either inducing
degradation of their target RNAs or repressing the production of their targets into protein. To fully
understand the roles miRNAs have on cellular processes, their target transcripts need to be identified. In
current protocols the one-to-one relation of the miRNA and the target RNA that exists in the regulatory
complex is lost, which impairs target identification. We intend to develop a new method in which the
miRNA and its target identity are maintained in a one-to-one ratio and subsequently measure these
interactions by using next generation sequencing techniques.
Signaling pathways in tuberculosis: elucidating mechanisms of macrophage recruitment to
granulomas
Dr. A.M. (Anna) Zakrzewska (f), 28-6-1975, Institute Biology Leiden, Molecular Cell biology
One third of the human population is infected with latent (“sleeping”) tuberculosis caused by
mycobacteria. Granuloma, a structure comprising infected and uninfected host immune cells, is the main
characteristic of this disease. Mycobacteria can survive within the granulomas for many years. This
project will investigate communication between immune cells within a single granuloma to expose the
mechanisms that allow for survival of mycobacteria in the host.
The role of retinoic acid in regulation of gene expression during lymph node formation.
Dr. S.A. (Serge) van de Pavert (m), 19-9-1971, VU Medical Centre - Molecular Cell biology and
Immunology
Autoimmune diseases are often associated with chronic inflammation and formation of lymphoid
structures. Retinoic acid plays an important role in lymph node development by altering the gene
expression profile of cells involved. I will explore how retinoic acid affects the gene expression profiles of
these cells, which could help to find drugs that efficiently treat chronic (auto-)inflammatory diseases.

Small circulating RNAs as predictors for bone loss
Dr. ing. B.C.J. (Bram) van der Eerden (m), 1-11-1970, Erasmus MC - Department of Internal
medicine
Osteoporosis is characterized by bone loss and elevated risk for fracture and its incidence is rising. It has
a strong impact on the health care budget and personal life due to pain and disability. Therefore, early,
easy detectable markers for bone loss are needed to be able to prevent damage later on. A novel
exciting group of molecules in the circulation that may serve as a risk indicator are small RNA molecules
(miRNAs). In this project, profiles of blood-based small RNAs from osteoporotic patients and healthy
controls will be compared, which may lead to the identification of novel biomarkers for the diagnosis of
osteoporosis.

Stromal transcriptomes from development to disease
Dr. T. (Tom) Cupedo (m), 4-5-1976, Erasmus MC - Department of Hematology
Our immune system battles infections and cancer from lymphoid organs called lymph nodes. These
lymph nodes are packed with immune cells that continuously interact with supportive stromal cells. The
researchers will define the transcriptomes of the specialized stromal cells in human lymph nodes in order
to understand how these cells coordinate both the development of the node and the fight against
infections.
Stochastic gene expression in the human pathogen Streptococcus pneumoniae:
Regulation of translational noise
Dr. J. (Jan-Willem) Veening (m), 26-12-1978, University of Groningen - Department of
Molecular Genetics
The human pathogen Streptococcus pneumoniae is a leading cause of bacterial pneumoniae and causes
millions of deaths in young children each year. Interestingly, many people carry this bacterium without
getting ill. In this project we will investigate the role of so-called biochemical „noise‟ as a potential source
that causes this bacterium to switch from its harmless mode to its pathogenic mode.

Source: http://www.genomics.nl/resources/documents/programmas/horizonb_7thcall_def.pdf

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