Overview
ROOTS – Role of telomeres and stem cells in ageing
Grant – ERC Advanced Grant
The impact of a globally ageing population cannot be overstated. It is expected that by the year 2025 over a billion individuals will be over 60 years of age. In order to develop strategies aimed to restore and maintain function in ageing individuals, a better understanding of the molecular pathways and biological processes that are involved in ageing and age-related disorders is urgently needed. One of the major mechanisms implicated in the decline of tissue function and ageing is the loss of tissue stem cells. This proposal is aimed at developing a better understanding of two fundamental aspects of stem cell biology: the molecular mechanisms that regulate self-renewal and differentiation and the role of telomere attrition and numerical chromosomal abnormalities in stem cell depletion. For both areas we propose to take advantage of recent improvements in DNA sequencing technology. We are specifically interested to measure telomere dysfunction and aneuploidy in stem cells and more differentiated cells, to identify genetic and other factors regulating human leukocyte telomere length and to study the role of telomere attrition in various leukocytes in relation to normal human ageing and pathology.
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| Principal Investigator: | Peter Lansdorp |
PDControl – Protein damage control: regulation of toxic protein aggregation in aging-associated neurodegenerative diseases
Grant – ERC Starting Grant
The worldwide aging population will lead to a dramatic increase in the number of people with Alzheimer’s disease and other incurable age-related neurodegenerative diseases over the next few decades. By 2050 over 115 million are expected to suffer from these devastating diseases. The major pathological hallmark of these disorders is the accumulation of aggregation-prone disease proteins in aggregates in the brain. To understand the disease mechanisms and to identify targets for treatment, the proposal aims at uncovering the cellular pathways that regulate disease-protein toxicity and aggregation (proteotoxicity). Opening up such exciting new avenues for research is our recent identification of a modifier of aggregation, which we named MOAG-4, as a general regulator of age-related proteotoxicity in worm (C. elegans) models for neurodegenerative diseases. MOAG-4 and its human counterpart SERF act independently of classical pathways that degrade proteins or prevent their aggregation, but their molecular role remains to be determined. The project hypothesizes that MOAG-4/SERF represents a new regulatory pathway of age-related proteotoxicity in neurodegenerative diseases.
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| Principal Investigator: | Ellen Nollen |
Macmodel – Harvesting the power of a new model organism: stem cells, regeneration and ageing in Macrostomum lignano
Grant – ERC Starting Grant
The ‘stem-cell theory’ of ageing posits that the functional decline in adult stem cells is one of the factors contributing to ageing. Importantly, the number of stem cells does not diminish with age in many tissues but rather there are intrinsic and extrinsic changes that affect their functionality. Is it possible to reverse these changes? Experiments in the emerging model Macrostomum lignano suggest that this is indeed the case. The research proposal aims at studying the molecular mechanisms underlying rejuvenation in M. lignano, and to further advance M. lignano as a model organism through development of missing genetic tools and resources. It will address how young, aged and regenerated worms differ in their gene and small RNA expression profiles, and what are the differences and variation levels between neoblasts of young, old and regenerated animals. The biological roles of the identified candidate genes and their effects on the lifespan and neoblast activity will be investigated. In parallel, methods for efficient transgenesis and gene manipulation will be developed, and the genome annotation improved.
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| Principal Investigator: | Eugene Berezikov |
Marriage – MARie CuRIe AGEing Network
Grant – Marie Curie Initial Training Networks
Website: http://ageingnetwork.eu/
The objective of this Network is to provide training in the biology of ageing to 11 Early Stage and 4 Experienced Researchers. The consortium has assembled a premier group of scientists that focus their activities on the molecular mechanisms that underlie ageing, with an emphasis on how maintenance of genomic integrity in self-renewing tissues is preserved under different metabolic rates. The key aim of this training program is the elucidation of the molecular pathway by which intrinsic genomic integrity can be modified by the extrinsic rate of metabolism. The Network consists of 10 full and 2 associated partners, representing 7 Member states and Switzerland and Canada, and include 4 commercial enterprises. Multiple complementary training schemes have been implemented in the Network. These include specific research projects (including multiple academic and industrial secondments), a variety of dedicated courses organized by the academic partners of the Network, and finally, training organized by the industrial partners of the Network. Trainees will become experts in the multidisciplinary field of ageing, and are expected to constitute future leaders in the field of ageing science and shape commercial activities in this realm.
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| Principal Investigator: | Gerald de Haan |
HEM_ID – HEMatopoietic cell IDentity : genetic and epigenetic regulation in normal and malignant hematopoiesis
Grant – Marie Curie Initial Training Networks
Website: http://www.hemid.eu/
The focus of Hem-ID is a highly integrated approach to study the functional interactions between the genetic regulatory circuits orchestrated by transcription factors –TFs-, (that direct the progressive cell type specification) and epigenetic mechanisms (that establish the “cellular memory” that fixes cell fate decisions during differentiation) in physiological hematopoiesis and in leukemia with the final goal of formulating novel diagnostic/prognostic markers and therapeutic approaches in treating leukemias. The strength of Hem-ID ITN lies in the high quality multidisciplinary -but strictly integrated- expertise and technological platforms covering the complete pathway from basic research to its clinical exploitation- contributed from both public Institutions and Private sector and made available to Hem-ID Fellows. Besides research, an integrated training program of scientific and complementary activities will be offered to HEM-ID Fellows that will complement and strengthen their career development.
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| Principal Investigator: | Gerald de Haan |
EuroCSCTraining – Eurocancer Stemcell Training Network
Grant – Marie Curie Initial Training Networks
Website: http://eurocsctraining.eu/
The recent identification of tumor initiating (TIC) or cancer stem cells (CSC) has opened a new area of research for scientists interested in cancer. Understanding the biology of cancer stem cells has already unraveled pathways and potential targets. However, accumulating data has underscored the complexity of the CSC research area and prompts hence the need for well-structured networks to provide expert platforms, rapid exchange of information to train future researchers in this new concept. 10 laboratories from 6 member states with 4 expert enterprises, all at the highest level of cancer stem cell research will unit in a European Cancer Stem Cell Training Network (EuroCSCTraining). Partners, from the public and private sector, have complementary expert experience in this new area, are active members of CSC research, and share dedication in training and dissemination. The main goal of the Network is to foster translaboratory and transPhD school training in this new area of Cancer Research. It is anticipated that the EuroCSCTraining network will create a multidisciplinary and multisector structure of training for a new area of research in cancer which will develop research in Europe, foster European collaborations and provide the basis to harmonise initial research training in cancer research amongst partner Institutions.
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| Principal Investigator: | Gerald de Haan |
Ploidynet – The impact of chromosomal instability on health: Molecular causes and consequences of aneuploidy
Grant – Marie Curie Initial Training Networks
Website: http://aneuploidy.nl/
Aneuploidy, an abnormal number of chromosomes, is a hallmark of cancer cells, affecting the majority of all human tumors. Aneuploidy arises when errors occur during mitosis, as the duplicated chromosomes are distributed between the two new daughter cells. Paradoxically, aneuploidy appears to have detrimental consequences for the physiology of untransformed cells in vitro, inhibiting rather than stimulating proliferation. This suggests that cancer cells have acquired mutations that help them cope with aneuploidy. Although it is clear that aneuploidy can contribute to cancer, the molecular consequences of aneuploidy remain elusive, as does how aneuploidy contributes to malignant transformation. The scientific aim of this network is to determine and compare the molecular consequences of different levels of aneuploidy, both in vivo and in vitro. Our network will train 9 Early Stage Career and 2 Experienced researchers in the aneuploidy field. To this aim, we are combining the expertise of labs that study the causes of aneuploidy with labs that induce aneuploidy in model organisms and study its consequences and also with labs that focus on the development of therapeutics that selectively kill aneuploid cell progeny. Trainees will thus become experts in the field of aneuploidy while rapidly building up a scientific network for themselves, putting them in an excellent position to become future leaders in this field.
| Research fields: | Chromosomal instability, causes and consequences of aneuploidy. |
| Principal Investigator: | Floris Foijer |
Composition, function, and dynamics of the yeast nuclear envelope
Grant – Vidi Scheme (NWO)
Safeguarding the chromatin, the nuclear envelope is arguably one of the most important borders within the eukaryotic cell. The nuclear envelope is a double membrane system consisting of an outer and an inner membrane. Traffic across the nuclear envelope is mediated by the nuclear pore complexes (NPCs), which span both the inner and outer membranes, and provide a selective channel for transport of macromolecules between the nuclear and the cytoplasmic compartments. To date it is largely unknown what role the NPCs play in acting as a selective gate for membrane proteins, and thus regulating the protein composition of the inner nuclear membrane. Also, the protein composition and function of the inner nuclear membrane is only beginning to emerge. In the yeast Saccharomyces serevisiae, we will determine the path and mechanism of transport of membrane proteins through the NPC using fluorescence microscopy. In a previous proteome analysis we have already identified a number of novel putative inner nuclear membrane proteins, and we will try to unravel their function using biochemical, proteomics and cell biology tools. The nuclear envelope is a highly dynamic membrane system and we will study the composition of the nuclear envelopes throughout the cell cycle, using quantitative proteome analysis of nuclear envelope membranes and pullouts isolated from synchronized cultures.
| Research fields: | Nuclear envelope, nuclear pore complex, membrane protein, Saccharomyces. |
| Principal Investigator: | Liesbeth Veenhoff |
Protecting the ends: characterizing the role of recombination at telomeres
Grant – Vidi Scheme (NOW)
The research proposed here aims to characterize the differences between telomeric recombination in pre-senescent cells and ALT cells, and to further explore the relationship between telomere length and recombination. Our approach combines classical genetic and molecular biological techniques, high-throughput genomic screening, and a powerful sequencing-based approach that will allow us to analyze both telomerase-mediated extension and recombination events in vivo at individual telomeres at nucleotide resolution. Our work will lead to a better understanding of DNA recombination and telomere maintenance, processes that are highly conserved throughout evolution with links to both cancer and ageing.
| Research fields: | Telomeres, DNA recombination, ALT, DNA break, telomerase. |
| Principal Investigator: | Michael Chang |
Cellular protein damage control: interactomic analyses of MOAG-4 in C. Elegans
Grant – Marie Curie Intra-European Fellowships for Career Development
Several age-related neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and Huntington’s diseases, are characterized by the formation of pathogenic proteins aggregates in the brain. Although some regulators have been identified, how aggregates form during aging is poorly understood. Recently, a modifier of aggregation, MOAG-4, was identified as a positive regulator of aggregation in C. elegans models for neurodegenerative diseases. The role of MOAG-4 is evolutionarily conserved in the human orthologs SERF1A and SERF2. MOAG-4/SERF appears to regulate age-related proteotoxicity through a previously unexplored pathway. Therefore, how this regulator works and in which pathway it acts needs to be established. The project aims at identifying proteins that physically interact and cooperate with MOAG-4 to drive protein aggregation. The results will reveal the mechanism by which MOAG-4 acts, and this will contribute to our understanding of how cells cope with toxic, aggregation-prone proteins during aging. Furthermore, new options will be opened for the development of therapeutic strategies to treat human neurodegenerative diseases.
| Research fields: | Protein aggregation |
| Principal Investigator: | Ellen Nollen |
Aging of the Nuclear Pore Complex: relating structure and function
Grant – ECHO ( Excellent Chemical Research – NWO)
The Nuclear Pore Complexes (NPCs) embedded in the nuclear envelope are the main sites of selective transport from and to the nucleus. Their function as a gateway to the cell’s chromatin is crucial to the signalling events that lead to the production of new proteins in a timely and controlled fashion. Many of the key steps in cell cycle regulation also build on selective entry of signal molecules into the nucleus. NPCs from aged tissues were reported to be less selective, more ‘leaky’ and this is expected to have major implications on the cell’s physiology. Building on a wealth of knowledge on what the molecular basis is for the selective properties of the NPC in young cells, we now aim to study these properties in the context of ageing. In Saccharomyces cerevisiae we will quantify the relative abundance of the NPC components and posttranslational modification as a function of chronological and replicative ageing. We will relate these observations to measurements of passive leak through the NPCs as a function of age. This data will be fed into a recently developed coarse-grained one-bead-per-amino-acid molecular dynamics model of the NPC. Based on the modelling results, predictions will be formulated how the observed changes in NPC structure and NPC function may be linked. Altogether this combined experimental and computational approach will result in a detailed description of the age-dependent changes in nuclear transport, which will be a first step in addressing its direct effects on ageing.
| Research fields: | Nuclear Pore Complex, Ageing, Proteomics, intrinsically disordered proteins, aminoacid-based coarsegrained modelling. |
| Principal Investigator: | Liesbeth Veenhoff |
