ERC FUNDED PROJECTS

Faithful repair of double stranded DNA breaks (DSBs) is essential, as they are at the origin of genome instability, chromosomal translocations and cancer. Cells repair DSBs through different pathways, which can be faithful or mutagenic, and the balance between them at a given locus must be tightly regulated to preserve genome integrity. Although, much is known about DSB repair factors, how the choice between pathways is controlled within the nuclear environment is not understood. We have shown that nuclear architecture and non-random genome organization determine the frequency of chromosomal translocations and that pathway choice is dictated by the spatial organization of DNA in the nucleus. Nevertheless, what determines which pathway is activated in response to DSBs at specific genomic locations is not understood. Furthermore, the impact of 3D-genome folding on the kinetics and efficiency of DSB repair is completely unknown. Here we aim to understand how nuclear compartmentalization, chromatin structure and genome organization impact on the efficiency of detection, signaling and repair of DSBs. We will unravel what determines the DNA repair specificity within distinct nuclear compartments using protein tethering, promiscuous biotinylation and quantitative proteomics. We will determine how DNA repair is orchestrated at different heterochromatin structures using a CRISPR/Cas9-based system that allows, for the first time robust induction of DSBs at specific heterochromatin compartments. Finally, we will investigate the role of 3D-genome folding in the kinetics of DNA repair and pathway choice using single nucleotide resolution DSB-mapping coupled to 3D-topological maps. This proposal has significant implications for understanding the mechanisms controlling DNA repair within the nuclear environment and will reveal the regions of the genome that are susceptible to genomic instability and help us understand why certain mutations and translocations are recurrent in cancer

1 999 750 €

Start date: 2017-03-01, End date: 2022-02-28

Alzheimer's disease, the most common cause of dementia in older people, is a devastating condition that is becoming a public health crisis as our population ages. Despite great progress recently in Alzheimer’s disease research, we have no disease modifying drugs and a decade with a 99.6% failure rate of clinical trials attempting to treat the disease. This project aims to develop relevant therapeutic targets to restore brain function in Alzheimer’s disease by integrating human and model studies of synapses. It is widely accepted in the field that alterations in amyloid beta initiate the disease process. However the cascade leading from changes in amyloid to widespread tau pathology and neurodegeneration remain unclear. Synapse loss is the strongest pathological correlate of dementia in Alzheimer’s, and mounting evidence suggests that synapse degeneration plays a key role in causing cognitive decline. Here I propose to test the hypothesis that the amyloid cascade begins at the synapse leading to tau pathology, synapse dysfunction and loss, and ultimately neural circuit collapse causing cognitive impairment. The team will use cutting-edge multiphoton and array tomography imaging techniques to test mechanisms downstream of amyloid beta at synapses, and determine whether intervening in the cascade allows recovery of synapse structure and function. Importantly, I will combine studies in robust models of familial Alzheimer’s disease with studies in postmortem human brain to confirm relevance of our mechanistic studies to human disease. Finally, human stem cell derived neurons will be used to test mechanisms and potential therapeutics in neurons expressing the human proteome. Together, these experiments are ground-breaking since they have the potential to further our understanding of how synapses are lost in Alzheimer’s disease and to identify targets for effective therapeutic intervention, which is a critical unmet need in today’s health care system.

2 000 000 €

Start date: 2016-11-01, End date: 2021-10-31

This project provides the first comparative historical analysis – local, national and transnational - of the Central African copperbelt. This globally strategic mineral region is central to the history of two nation-states (Zambia and Democratic Republic of Congo (DRC)), as well as wider debates about the role of mineral wealth in development. The project has three interrelated and comparative objectives. First, it will examine the copperbelt as a single region divided by a (post-)colonial border, across which flowed minerals, peoples, and ideas about the relationship between them. Political economy created the circumstances in which distinct political cultures of mining communities developed, but this also involved a process of imagination, drawing on ‘modern’ notions such as national development, but also morally framed ideas about the societies and land from which minerals are extracted. The project will explain the relationship between minerals and African polities, economies, societies and ideas. Second, it will analyse how ‘top-down’ knowledge production processes of Anglo-American and Belgian academies shaped understanding of these societies. Explaining how social scientists imagined and constructed copperbelt society will enable a new understanding of the relationship between mining societies and academic knowledge production. Third, it will explore the interaction between these intellectual constructions and the copperbelt’s political culture, exploring the interchange between academic and popular perceptions. This project will investigate the hypothesis that the resultant understanding of this region is the result of a long unequal interaction of definition and determination between western observers and African participants that has only a partial relationship to the reality of mineral extraction, filtered as it has been through successive sedimentations of imagining and representation laid down over nearly a century of urban life in central Africa.

1 599 661 €

Start date: 2016-07-01, End date: 2021-09-30

This proposal outlines a number of projects in public economics, with links to other fields such as macro, real estate, labor, and gender economics. The projects evolve around several large administrative datasets from the UK and Denmark, and they advance approaches and methodologies that have recently been developed in public economics into new areas. There is a strong public policy focus running through the proposal, including tax policy, transfer policy, family policy, and indirectly monetary policy. The objective is to achieve a comprehensive understanding of how government interventions affect two key markets: the housing market and the labor market. The project is divided into two themes. The first theme focuses on the housing market and is divided into three subprojects. The first project investigates the effects of mortgage interest rates on leverage and house prices, and it develops a new quasi-experimental method for estimating the elasticity of intertemporal substitution in consumption, a crucial parameter for many public policies. The second and third projects investigate housing market responses to different tax policies, focusing on how such responses are magnified by liquidity constraints and leverage. The second theme focuses on the labor market and is divided into two subprojects. The first project studies secular changes in gender inequality and the underlying sources of those changes, focusing mainly on the effects of child rearing on gender inequality. The project explores the underlying mechanisms driving child-related inequality, including gender identity norms and family policies. The second project proposes a new way of estimating macro labor supply elasticities that integrates taxes and public expenditures, and it develops a theoretical framework to draw policy implications from those estimations.

1 294 699 €

Start date: 2016-06-01, End date: 2021-05-31